Organometallic Anti-Tumor Agents: Targeting From Biomolecules To Dynamic Bioprocesses

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Published on 04 April 2023. Downloaded by Sun Yat-Sen (Zhongshan) University on 4/5/2023 9:58:57 AM.
Organometallic anti-tumor agents: targeting from

biomolecules to dynamic bioprocesses
Cite this: DOI: 10.1039/d2cs00757f
Kun Peng, † Yue Zheng, † Wei Xia * and Zong-Wan Mao *
The great clinical success of cisplatin and its derivatives has convinced people that metal complexes
could play a more significant role in human cancer therapy. However, targeting and drug resistance are
still two dominant problems that need to be urgently solved for metallodrugs’ efficacy and clinical
translation. As an important component of metal complexes, organometallics have been experiencing
rapid development in recent years. Compared with platinum drugs, emerging anti-tumor
organometallics targeting dynamic bioprocesses provide an effective strategy to overcome conventional
problems. This review focuses on burgeoning anti-tumor strategies and provides up-to-date advances in
anti-tumor organometallics development based on their action mechanisms. Specifically, important
tumor-overexpressed proteins and nucleic acids as organometallics’ anti-tumor targets are
systematically presented, followed by organometallics that exert their anti-tumor activity by perturbing
tumor intracellular energy/redox/metal/immune homeostasis. Finally, nine cell death pathways including
Received 14th December 2022 apoptosis, paraptosis, autophagy, oncosis, necrosis, necroptosis, ferroptosis, pyroptosis, and
DOI: 10.1039/d2cs00757f immunogenic cell death (ICD) that can be induced by organometallics are reviewed, and their
morphological and biochemical features are summarised. This review at the interface of chemistry,
rsc.li/chem-soc-rev biology, and medicine aims to enlighten the rational development of organometallic anti-tumor agents.
1. Introduction
The discovery of the first organometallic compound, Zeise’s
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, salt, in 1827, is of historical importance in organometallic
State Key Laboratory of Oncology in South China, Sun Yat-Sen University, chemistry, an interdisciplinary research field that grew out of
Guangzhou 510275, P. R. China. E-mail: cesmzw@mail.sysu.edu.cn,
an exchange between the classic subdivisions of organic and
xiawei5@mail.sysu.edu.cn
† Kun Peng and Yue Zheng contributed equally to this work. inorganic chemistry. Organometallics, a class of compounds
Kun Peng started his bioinorganic Yue Zheng obtained her bachelor’s
chemistry study from Zhengzhou degree in chemistry from Ocean
University, China, where he University of China in 2015, and
obtained his MS in 2015 under received her PhD in inorganic
the supervision of Prof. Jin’an chemistry from Sun Yat-Sen
Zhao. Then, he joined Prof. University under the supervision
Ulrich Schatzschneider’s group of Prof. Zong-Wan Mao in 2020.
and received his PhD in 2020 Now she is a postdoctoral fellow in
from Julius-Maximilians-Univer- Prof. Erwei Song’s group at Sun
sität Würzburg, Germany. Curr- Yat-Sen Memorial Hospital. Her
ently he is a postdoctoral fellow research interests mainly focus on
in the group of Prof. Zong-Wan biomacromolecule-targeted and
Kun Peng Mao at Sun Yat-Sen University. Yue Zheng tumor microenvironment-reversed
His research interests mainly metallodrugs.
focus on metallodrug development and inorganic click (iClick)
reactions.
This journal is © The Royal Society of Chemistry 2023 Chem. Soc. Rev.
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Review Article Chem Soc Rev
with at least one covalent metal–carbon bond, have been widely as potential anti-tumor chemotherapeutics.11,12 A timeline of
used in catalytic, stoichiometric, and biological chemistry. To important milestones in the history of bio-organometallic
date, 13 Nobel Prizes have been awarded in the field of chemistry research is summarised in Fig. 1.
organometallic chemistry. In particular, Dorothy Hodgkin was Due to the widespread success of cisplatin and its six
awarded the Nobel Prize in Chemistry in 1964 for solving the derivatives in cancer treatment, there has been a rapid expan-
atomic structure of molecules such as penicillin and vitamin sion in the research and development of metal-based anti-
B12 by X-ray crystallography. The elucidation of the crystal tumor complexes over the past several decades. However, it
structure of coenzyme vitamin B121 demonstrated that organo- should be noted that drug resistance and side effects are still
metallic compounds hold an important place in life science two major challenges that limit the broad application of
and have attracted interest from biology and medicine.2 In metallodrugs.13 The mechanisms of drug resistance and side
1985, the emerging field of ‘‘bio-organometallic chemistry’’ effects are often multifactorial and complicated. Taking cispla-
proposed by Gérard Jaouen further evoked the development tin as an example, its relatively sole DNA binding action mode
of organometallics in research fields of medicine, metallopro- facilitates tumor cells to become resistant, while the lack of
teins and bio-probes.3,4 tumor selectivity leads to its cytotoxic side effects. Therefore,
The medicinal application of organometallics can be dated the design of metal complexes that target cancer-specific bio-
back to 110 years ago when an organo-arsenic compound, molecules or biological processes is a promising approach for
salvarsan, was utilised for the treatment of syphilis.5 Although new anti-tumor drug development. Cancer-specific biomole-
salvarsan was later totally replaced by penicillin after the cule targeting of metal complexes could enhance anti-tumor
Second World War, this organometallic drug indeed pioneered selectivity and efficacy, which reduces cytotoxic side effects.
the era of ‘‘chemotherapy’’ – a term coined by Paul Ehrlich, who Furthermore, targeting multiple cancer-related biological pro-
discovered salvarsan. In the early 1950s, the discovery of the cesses would provide complex anti-tumor action modes and
‘‘star’’ compound, ferrocene, significantly accelerated the make it difficult for cancer cells to become drug-resistant.14
development of bio-organometallics.6 Since then, ferrocene Compared to classical organic small molecules and metal
and its derivatives have gained enormous attention for their coordination complexes, organometallic compounds have
anti-anemia, anti-microbial and anti-tumor properties.7,8 In many unique advantages as anti-tumor agents. Based on the
1979, Köpf and Köpf-Maier found that another metallocene, ligand type, the majority of the reported anti-tumor organome-
titanocene dichloride, had excellent anti-tumor properties, and tallic compounds can be classified into six categories: metal
this organometallic compound even entered clinical trials in cyclopentadienyl (Cp),6,15 metal arene,16–18 cyclo-metalated
1993.9,10 The discovery of titanocene dichloride is considered as complex,19–22 metal carbonyl,23 metal carbene24–26 and metal
a major milestone in the history of organometallics develop- acetylide (Fig. 2).27,28 Because of the presence of a metal–carbon
ment, indicating the tremendous potential of organometallics bond and p-bound arenes, these organometallic compounds
for cancer treatment. Subsequently, an increasing number of exhibit high kinetic stability. In addition, scientists could
organometallics have been rationally designed and synthesised rationally design organometallic compounds via the
Wei Xia received his bachelor’s Zong-Wan Mao earned his

degree in biochemistry from bachelor’s degree from Sichuan
Peking University in 2006 and University in 1982, and received
his PhD in chemical biology his MS and PhD from Nanjing
from the University of Hong University under the supervision
Kong in 2011. Then he joined of Prof. Wen-Xia Tang in 1991
Prof. Timothy A. Springer’s lab and 1994, respectively. Then he
as a postdoctoral fellow at joined Prof. Liang-Nian Ji’s group
Harvard Medical School in as a postdoctoral fellow at Sun
Boston. After three years of Yat-Sen University. Two years
training, he began as an later, he received the Alexander
Associate Professor at Sun Yat- von Humboldt Fellowship, and
Wei Xia Sen University in 2014. He was Zong-Wan Mao studied with Prof. Rudi van
promoted to a full professor in Eldik at the University of
2022. His research interests include the inorganic chemical Erlangen-Nuremberg, Germany. He was appointed as an
biology of metalloproteins and organometallic therapeutics in associate professor at Sun Yat-Sen University in 1999, and was
anticancer and antibacterial therapy. promoted to full professor in 2004. He is also the fellow of the
Royal Society of Chemistry (FRSC). His research interests include
metallodrugs, molecular probes and biological imaging, chemical
biology of metal ions and metalloenzyme chemistry.
Chem. Soc. Rev. This journal is © The Royal Society of Chemistry 2023
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Fig. 1 Important milestones in the history of the development of bio-organometallic complexes.
cellular homeostasis perturbation by organometallic com-

pounds induces cancer cell death. Nine classical and reported
cell death pathways that can be activated by organometallic
compounds are summarised in the last part of the review. In
the meantime, the molecular structural design rationales and
commonly used research methods in bio-organometallic chem-
istry are also included, with the aim of facilitating the rational
development of anti-tumor organometallic compounds in the
future.
2. Anti-tumor organometallics
targeting tumor-specific biomolecules
Rapid growth, metastatic potential, and hypoxic and acidic
tumor microenvironment are the major characteristics of
Fig. 2 The major classification of current anti-tumor organometallics
based on their ligand type. tumor cells. Typically, the cellular production of biomolecules,
such as cell surface receptors, membrane transporters, intra-
cellular enzymes, and certain nucleic acids, is often elevated in
implementation of different functional ligands to achieve spe- tumor cells (Fig. 3). Therefore, these cancer-specific bio-
cific targeting and/or synergistic anti-tumor efficacy. Further- molecules are ideal targets for the development of anti-
more, recent studies have shown that some organometallic tumor drugs.
compounds can perturb cancer cell homeostasis and activate As an important research direction for current anti-tumor
various cell death pathways, indicating different modes of agent development, targeted therapy has gained enormous
action. Taken together, organometallic compounds can be used attention from bio-organometallics scientists. Naturally, the
as a unique class of therapeutic agents for cancer treatment. strong binding affinity of the transition metal centres endows
In this review, we mainly focus on the anti-tumor mechan- organometallic complexes with certain enzyme and nucleic
isms of transition metal-based organometallic compounds. We acid targets. Apart from this inherent property, a major strategy
began with the classical organometallic compounds that can from a drug design perspective that is currently widely applied
target cancer-specific biomolecules. Since increasing evidence to generate ‘‘targeted’’ organometallic anti-tumor complexes is
indicates that organometallic compounds also exhibit unique the introduction of tumor-overexpressed biomolecule-targeting
anti-tumor activity by perturbing energy/redox/metal/immune groups into organometallic frameworks to enhance drug
homeostasis in cancer cells, these unique modes of action are uptake and selectivity towards tumors over healthy cells. In
summarised in the second part of this review. Furthermore, this section, four types of organometallics’ anti-tumor
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multivitamin transporter (SMVT) were used to examine the

cytotoxicity of these ruthenium complexes. Complexes 2-1
and 2-2 demonstrated higher activity against the SMVT-
overexpressing SW620 cell line compared to COLO205 and
HCT116 cell lines, which feature approximately 3-fold lower
SMVT expression levels. The cytotoxicity of complexes 2-1 and
2-2 towards SW620 was also higher than that of the reference
non-biotinylated compound and the organic biotin ligand.29

Later, Valente and Garcia et al. synthesised another class of
CpRu complexes 2-3–2-5 with a biotin functional group
(Fig. 4(a)). In MDA-MB-231 cell line expressing high levels of
biotin receptors, the cytotoxicity of these biotinylated com-
plexes correlated well with their cellular uptake. All these
Fig. 3 The cellular distribution of representative tumor-specific bio-
complexes were mainly located on the cell membrane due to
molecules (CA IX: carbonic anhydrase IX; ASNS: asparagine synthetase;
CDKs: cyclin-dependent kinases; TrxR: thioredoxin reductase; tRNA: the binding of the biotin group to its receptors.30 Importantly,
transfer RNA; HDACs: histone deacetylases; COX: cyclooxygenases; GSTs: complexes 2-3–2-5 overcame cisplatin-resistance in MDA-MB-
glutathione S-transferases; GSK-3: glycogen synthase kinase 3; KDM5A: 231 cell line by B9–16 fold compared with cisplatin. Their
lysine-specific demethylase 5A; PARP-1: poly(ADP-ribose) polymerase 1; impressive anti-tumor activity is attributed to the strong selec-
G4 DNA: G-quadruplex DNA).
tive inhibiting ability for P-glycoprotein, a transporter belong-
ing to the adenosine triphosphate-binding cassette (ABC)
biomolecular targets are summarised, namely receptors and superfamily, which is responsible for pumping anti-cancer
transporters that are overexpressed on the cancer cell surface, drugs out of tumor cells.30,31 Furthermore, an in vivo study
tumor-related enzymes and proteins inside cancer cells, using a zebrafish model showed that these biotinylated ruthe-
G-quadruplex DNA (G4 DNA) with functions in various cancers, nium complexes caused much less toxic side effects than the
and transfer RNA (tRNA) that is upregulated in highly meta- corresponding reference complexes without biotin, suggesting
static breast cancer cells. Correspondingly, representative good in vivo tolerability through this biotin-targeting approach.
organometallic complexes and their anti-tumor properties are It is worth noting that all of the above-mentioned biotinylated
discussed. complexes 2-1-2-5 retain the specific recognition between avi-
din and the biotin moiety, although their binding affinity is
slightly lower than that of biotin itself.29–31 Encouragingly, the
2.1 Receptors and transporters on the cancer cell surface crystal structure of avidin–biotinylruthenocene complex 2-6 was
Biotin (vitamin B7) is an essential vitamin for cellular metabo- obtained to help us account for the reduced binding affinity: as
lism of carbohydrates, amino acids, and lipids. Since tumor shown in Fig. 4(b), after ruthenocene conjugation, strong
cells often require a high level of biotin, and this vitamin can hydrogen bonds between the biotin carboxyl moiety and avidin
only be exogenously supplemented, biotin has been widely no longer existed. Instead, weaker p–p stacking interactions
utilised as a tumor-targeting group. For example, the Hartinger between two Cp rings of 2-6 and avidin side chains Ser73 and
group conjugated biotin with a Ru–arene moiety to generate Arg114 were observed.32
two Ru–arene complexes 2-1 and 2-2 (Fig. 4(a)).29 Three tumor High levels of glucose uptake and metabolism are hallmarks
cell lines with different expression levels of sodium-dependent of tumor cells and are vital for tumor growth and homeostasis
Fig. 4 (a) Chemical structures of representative biotin-functionalized anti-tumor organometallics; (b) the crystal structure of avidin in complex with 2-6
(PDB: 4I60) and key active binding sites.32
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Fig. 5 (a) Representative key binding sites between human GLUT3 and D-glucose determined by crystal structure (PDB: 4ZW9);34 (b) chemical
structures of representative organometallics functionalized with glucose or galactose as the tumor targeting group.
maintenance. Consequently, many glucose transporters healthy fibroblast cells was not affected by quercetin, indicating
(GLUTs) and receptors are usually overexpressed in many a GLUT-associated endocytosis cellular uptake mechanism of
human cancer cells.33 Furthermore, owing to the biocompat- this galactose-functionalized complex.36 Another glucose-
ibility and hydrophilicity of the glucose group, the functiona- conjugated gold(III) complex 2-9 developed by the Zou group
lization of anti-tumor organometallics with glycosylated ligands further proved the involvement of GLUT in compound endocy-
could be a feasible strategy to improve tumor targeting ability. tosis (Fig. 5(b)).37 When complex 2-9 was co-treated in tumor
In 2015, the crystal structure of human GLUT3 bound to cells with dynasore (a dynamin-dependent endocytosis inhibi-
D-glucose was successfully determined by the Yan group, from tor), or chlorpromazine (a clathrin-mediated endocytosis
which an outwards-occluded glucose-GLUT3 conformation blocker), or phlorizin (a GLUT inhibitor), respectively, the
involved in a series of hydrogen bonds and polar and hydro- cellular uptake content and photocytotoxicity of complex 2-9
phobic interactions was displayed (Fig. 5(a)),34 providing a were consistently decreased. Interestingly, this alkyl complex is
deeper structural understanding of this targeting strategy. stable under biological conditions in the dark; however, upon
Recently, the Che group reported a glucose-conjugated light irradiation, it can undergo b-hydride elimination to
platinum(II) terpyridyl acetylide 2-7 (Fig. 5(b)).35 The hydrophi- release the alkyl ligand and form a gold(III)-hydride intermedi-
lic glucose unit endows this complex with good water solubility. ate that can be rapidly converted into the bioactive [Au(III)–S]
In the cell culture medium, complex 2-7 underwent self- adduct. Meanwhile, the remaining complex 2-9 can serve as a
assembly into nanoparticles. As a result, this complex failed catalyst to facilitate the reduction of [Au(III)–S] to more cytotoxic
to enter cells through GLUT, which indicates that self- Au(I) species under light excitation. Through glucose functio-
aggregation is a non-negligible factor to be considered for this nalization and photo-induced b-hydride elimination and
targeting approach. Nevertheless, such aggregation facilitated reduction, complex 2-9 achieved high tumor selectivity, promis-
its uptake into lung cancer cells via energy-dependent endocy- ing photocytotoxicity, and efficient thioredoxin reductase
tosis, as evidenced by the strong reduction in cellular Pt (TrxR) inhibition, eventually leading to strong in vivo antian-
accumulation upon incubation at low temperature or inhibi- giogenesis, anti-tumor efficacy, and low off-target toxicity.37
tion of endocytosis by hypertonic sucrose. This complex is then In recent years, the conjugation of anti-tumor organometal-
transformed into other superstructures through cleavage of the lics with targeting peptides has emerged as a promising strat-
glycosidic linkage by b-glucosidase in endosomes/lysosomes egy for solubility improvement, selectivity enhancement, and
and further aggregated in mitochondria to result in lysosomal alleviation of side effects. The Metzler-Nolte group created a
integrity disruption, autophagy intervention, mitochondrial great deal of such organometallic–peptide bioconjugates dur-
membrane depolarisation, and necrotic cell death. Complex ing the past decade.38 For example, a series of pentamethylcy-
2-7 showed selective cytotoxicity against tumor cell lines rela- clopentadiene (Cp*) rhodium(III) complexes conjugated with
tive to normal fibroblasts. tyrosine-containing G-protein-coupled receptor (GPCR) pep-
Ruffo and Merlino et al. also prepared a set of platinum(II) tides were successfully synthesized under biologically friendly
complexes directly coordinated with galactose or glucose deri- conditions (Fig. 6(a)).39 Compared with the native peptide
vatives via C1 or C6 atom.36 Among these, complex 2-8 [Tyr1]-leu-enkephalin, the binding affinities of the Cp*Rh-
(Fig. 5(b)) exhibited the best selectivity towards SVT2 tumor peptide complex 2-10 towards d- and m-opiate receptors (DOR
cells over the corresponding immortalised murine fibroblast and MOR, respectively) were generally reduced. Still, complex
BALB/c-3T3 normal cells. The cytotoxicity of this complex to 2-10 can be labeled as an agonist with the nanomolar level of
cancer cells was reduced in the presence of quercetin, a well- binding potency. In addition, this organo-rhodium(III) complex
known inhibitor of glucose transporters, while its activity on showed cytotoxicity very similar to that of non-metal peptides
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Fig. 6 (a) Chemical structures of representative anti-tumor organometallics functionalized with certain peptides as the tumor targeting group; (b) the
general binding mode between avb3 integrin and a cyclic RGD containing peptide determined by crystal structure (PDB: 1L5G).41
against opioid receptor-positive MCF-7 and HT-29 cell lines, complex 2-12 exhibited non-cytotoxic effects towards a variety
indicating that the anti-tumor activity of this metal–peptide of tumor cell lines, this complex showed good cytostatic activity
conjugation 2-10 might be directly related to its binding pep- against SKOV-3 cells, whereas the reference compound without
tide, and the function of the native peptide could be mainly the RGD peptide was not active.
retained after such a bioconjugation.39 More recently, an RGD-containing peptide was used for the
Recently, an emissive iridium(III) complex 2-11 tethered to construction of a palladium complex that can target integrin-
JMV594, a bombesin pseudo-peptide analogue acting as the overexpressing tumor cells.43 Importantly, this targeted palla-
gastrin-releasing peptide receptor (GRPR) antagonist, has been dium compound can activate the bioactivity of N-heterocyclic
constructed (Fig. 6(a)).40 Owing to the high affinity and speci- carbene (NHC)–Au(I)–phenylacetylide complex 2-13 (Fig. 6(a))
ficity of the JMV594 group to the GRPR, this complex enables by triggering transmetalation reactions. The RGD-peptide func-
the discrimination of GRPR-positive A549 cancer cells from tionalized palladium complex was selectively recognised and
GRPR-negative normal LO2 cells through cellular imaging accumulated in integrin-overexpressing tumor cells, providing
experiments. Importantly, the cellular uptake level of complex opportunities for in situ replacement of the phenylacetylide
2-11 was tremendously lower in GRPR-knockdown A549 cells, ligand from complex 2-13 with a labile ligand. Consequently,
validating that the GRPR is the actual target of this complex cytotoxicity of the gold(I) moiety through TrxR inhibition was
inside the cell.40 observed. Meanwhile, since the RGD-palladium(II) complex is
The Arg–Gly–Asp (RGD) peptide has been widely applied as a less favourable for the integrin low-expressing normal cell line
tumor targeting group for cancer cells with high levels of LO2, complex 2-13 did not undergo transmetalation and
integrin due to their high binding affinity. As previously illu- retained its original non-toxic form due to the low palladium
strated from the crystal structure of the extracellular region of content in normal cells.
integrin avb3 in complex with an RGD containing peptide, the Two-thirds of breast tumor cells are defined as hormone-
RGD sequence is able to strongly bind at the major interface dependent, in which the estrogen receptor is presented.44
between av and b3 subunits through extensive contacts, includ- Tamoxifen is a leading drug as an estrogen receptor modulator,
ing hydrogen bonds, hydrophobic interactions, and polar inter- and can form a number of hydrogen bonds and hydrophobic
actions (Fig. 6(b)).41 Sarli and coworkers designed and contacts as determined by the crystal structure of the complex
synthesised a cyclo-metalated platinum(II) conjugate 2-12 with of estrogen receptor-a ligand-binding domain and the tamox-
c(RGDyk) peptide as the guiding unit to cancer cells ifen derivative (Fig. 7(a)).45 To selectively treat against estrogen
(Fig. 6(a)).42 Cellular uptake of complex 2-12 and its reference receptor-positive breast cancers, the initial strategy applied by
complex without the RGD peptide identified the functionality organometallics was the functionalization of the CpM moiety
of this targeting peptide, since the cytotoxicity of complex 2-12 (M = Ti, Fe, Re, Ru) with tamoxifen to rationally construct
to U87 glioblastoma cells with high avb3 integrin receptors was estrogen receptor targeting organometallic complexes in the
considerably stronger than that of the reference complex. In 2000s (Fig. 7(b)).46 After organometallic modifications, the Ti-,
addition, the cellular uptake of complex 2-12 in U87 cells was Fe- and Re-centred complexes 2-14-2-16 demonstrated weaker
found to be much higher than that in HeLa cells with low relative binding affinity for the estrogen receptor than tamox-
integrin content. Inhibitor studies proved that complex 2-12 ifen, presumably because the replacement of a benzene ring in
entered U87 cells through endocytosis, while its reference tamoxifen by those organometallic moieties increased steric
complex utilised other pathways. In addition, although hindrance.47 Surprisingly, the Ru-centred complex 2-17
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simulation for complex 2-18 with the aromatase enzyme indi-

cated that their interaction is highly favourable from an ener-
getic perspective.52 However, subsequent work from the same
group suggested that the CpRu complex 2-19 coordinated with
one nitrile group of anastrozole (Fig. 7(b)) cannot affect the
activity of aromatase due to the bulkiness of the additional
triphenylphosphine group, regardless of its good in vitro and
in vivo anti-tumor activities.53

Epidermal growth factor receptors (EGFR) are dimeric
transmembrane proteins and are members of the receptor
tyrosine kinase (RTK) family. EGFR can induce cancer-related
downstream effectors and drug ‘‘off-target’’ resistance via upre-
gulation of DNA repair mechanisms, and they are often
overexpressed in a large set of human cancer cells. Given that,
several ruthenium(II) arene organometallic complexes
with EGFR-inhibiting ligands such as tyrphostin derivatives54
and analogues of gefitinib (an anti-tumor drug acting through
Fig. 7 (a) The general binding mode between the estrogen receptor-a EGFR inhibition),55 have been prepared over the past several
ligand-binding domain and a tamoxifen derivative determined by crystal
years. Recently, the Wang group reported a set of cyclometa-
structure (PDB: 5W9C);45 (b) chemical structures of representative anti-
tumor organometallics functionalized with tamoxifen or anastrozole for
lated platinum(II) complexes 2-20 and 2-21 bearing 4-
targeted treatment of estrogen receptor-positive breast cancers. anilinoquinazoline (the core of the well-known EGFR inhibitors
gefitinib and erlotinib) derivatives as the EGFR targeting group
(Fig. 8(a)).56 Based on the crystal structure of the EGFR–erloti-
featured an unprecedentedly high relative binding affinity with nib complex (Fig. 8(b)),57 the docked molecular models of
the estrogen receptor, which is even stronger than that of complex 2-21 at the ATP-binding cleft of the EGFR kinase
hydroxytamoxifen. Since the Z isomer of tamoxifen has been demonstrated that complexation generally preserves important
shown to be the most effective for estrogen recognition, its hydrogen bonds between the inhibition ligand and Lys721,
great stability of the Z isomer determined by molecular model- Met769, and Thr766 of EGFR. Moreover, the platinum moiety
ing studies may account for the high relative binding affinity of provided additional hydrophobic contacts with Val693 and
complex 2-17.48 Among these organometallic–tamoxifen con- Leu694 at the EGFR surface. Consequently, complexes 2-20
jugations, complexes 2-16 and 2-17 showed no improvement in and 2-21 turned out to have similar inhibitory potency against
the antiproliferative activity towards estrogen receptor-positive EGFR as gefitinib with IC50 values at the nanomolar level. In
MCF-7 cells relative to tamoxifen, and no activity on receptor- addition, such bioconjugation confers these two complexes
negative MDA-MB-231 cells,44,48 whereas the titanocene deriva- stronger binding affinity to DNA, especially G-quadruplex (G4)
tive 2-14 displayed an estrogenic effect.49 In terms of the DNA. Complexes 2-20 and 2-21 exhibited more promising
ferrocene-based complex 2-15, strong cytotoxicity was observed
in both tumor cell lines, regardless of estrogen receptor
expression.47 These results indicated the crucial role of the
organometallic moiety in their drug efficacy, which is perhaps
due to the tunable redox properties of the metal intrinsic
character.50,51
Apart from tamoxifen, aromatase inhibitors such as anastro-
zole could also achieve selective treatment for estrogen
receptor-positive breast cancers, since aromatase inhibitors
could deprive these cells of estrogens by preventing the
aromatase-catalysed production of this hormone from andro-
gens. Recently, the Castonguay group developed a class of
ruthenium(II) arene organometallic complexes equipped with
the aromatase inhibitor anastrozole as a targeting group.52
Among these, complex 2-18 (Fig. 7(b)) turned out to be the
most stable complex in cell culture media with the highest
cellular uptake and much stronger cytotoxicity towards two
estrogen receptor-positive human breast tumor cell lines
Fig. 8 (a) Chemical structures of representative organometallic com-
(MCF-7 and T47D) than anastrozole. In addition, complex plexes targeting EGFR- and PTK-7, respectively; (b) representative key
2-18 was able to weaken the aromatase catalytic activity in binding sites between erlotinib and EGFR determined by crystal structure
aromatase-overexpressing H259R cells. In addition, docking (PDB: 1M17).57
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cytotoxicity against a variety of tumor cell lines than cisplatin trastuzumab to construct complex 2-24 (Fig. 9(b)).64 Since there
and gefitinib, and showed 9–30 fold higher inhibitory is a large interface between antibody and HER2, the introduc-
activity on EGF-stimulated MCF-7 tumor cells compared to tion of a much smaller Au–carbene fragment is supposed to not
HEK293 healthy cells.56 greatly perturb their interaction. As expected, compared to
The Veige group reported the bioconjugation of an NHC– trastuzumab, complex 2-24 retained similar specificity and
gold(I) complex with the DNA aptamer sgc8c (Fig. 8(a)). Such a binding affinity to HER2, which is overexpressed in 20–30%
DNA aptamer is capable of recognising and targeting protein of human breast cancers. As a result, this complex displayed
tyrosine kinase 7 (PTK-7), a transmembrane receptor protein superior inhibitory ability on HER2-positive SKBR3 breast
overexpressed in CCRF-CEM-leukaemia cells. Upon conjuga- cancer cells relative to HER2-negative MDA-MB-231 and
tion, the cytotoxicity of complex 2-22 was 13-fold higher than MCF10A healthy breast cells. Moreover, the antiproliferative
that of the gold precursor. Furthermore, complex 2-22 featured activity of complex 2-24 was also moderately increased in
good cell selectivity with strong cytotoxicity to CCRF-CEM cells comparison with that of its chlorido precursor 2-23.64
and non-toxicity to K562 cells. These results highlight the Another anti-tumor gold(I)-HER2 antibody complex 2-26 was
tumor-targeting ability of the sgc8c aptamer.58 later reported by Contel and Lewis et al. via the reaction of the
In recent years, antibodies have emerged as a rapid growing activated NHS ester unit with trastuzumab lysine residues
anti-cancer drug class for targeted therapy. Antibodies often (Fig. 9(b)).65 The binding affinity of complex 2-26 with HER2
hold specific binding ability to antigens which are unique and (EC50 = 1.13 ! 0.14 nM) is slightly decreased compared to that
over-expressed in many human tumor cells.59,60 To date, most of unmodified trastuzumab (EC50 = 0.22 ! 0.03 nM), which is
of the antibody-conjugated drugs in preclinical and clinical hypothesized to be due to the non-site selective modification of
development are mainly based on organic molecules, and the trastuzumab via lysine conjugation. Importantly, the EC50
pioneering efforts on the development of such complexes based values of complex 2-26 against HER2-positive MCF-7 and BT-
on metallodrugs started from conjugation of antibodies 747 cancer cells are in the low micromolar range, which is more
with cisplatin to enhance its DNA replication inhibition and than ten times lower than that of the gold(I) precursor 2-25 and
tumor targeting ability.61,62 As for the anti-tumor organometal- trastuzumab. Complex 2-26 also features better tumor selectiv-
lic–antibody conjugation, the first example is perhaps the ity than complex 2-25, trastuzumab, and the standard com-
gold(I) carbene complex functionalized with an engineered pound auranofin.65
trastuzumab, which is a human epidermal growth factor recep- Very recently, taking account of the intriguing catalytic
tor 2 (HER2) antibody also known as herceptin. The crystal property of organometallics, our group rationally designed
structure of the extracellular region of HER2 in complex with the first ruthenium(II)-affibody catalyst hybrid 2-28 for in situ
trastuzumab (Fig. 9(a)) demonstrated that trastuzumab inter- prodrug activation and selectively killing HER2-positive cancer
acts with HER2 by binding to its three juxtamembrane regions cells.66 Complex 2-28 was prepared by conjugating a CpRu
(residues 557–561, 570–573, and 593–603).63 In this work, a catalyst 2-27 with an HER2 affibody through a maleimide-
chemo-selective cysteine conjugation synthetic strategy was thiol coupling reaction (Fig. 9(b)). Because of the catalytic
successfully employed to link the gold carbene moiety with nature of the ruthenium(II) unit, complex 2-28 can selectively
Fig. 9 (a) The crystal structure of the extracellular domain of HER2 (blue) complexed with the trastuzumab antigen-binding fragment (yellow) (PDB:
1N8Z);63 (b) chemical structures of representative anti-tumor organometallics functionalized with trastuzumab or HER2 affibody for targeted treatment
of HER2-positive cancer cells.
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accumulate on the HER2-positive cancer cell surface and act as 30 resembled the hydrogen-bonding pattern of the ATP adenine
a catalyst for in situ activation of an N-allyloxycarbonyl-caged base and formed one hydrogen bond between the imide NH
gemcitabine prodrug to the active drug gemcitabine. As a group and the backbone carbonyl oxygen atom of Glu121
result, both complex 2-28 and the activated gemcitabine show within the hinge region. The hydroxy group of (S)-2-30 estab-
synergistic anti-tumor efficacy via blocking the HER2 signalling lishes two additional hydrogen bonds with ordered water
pathway and damaging DNA. Encouragingly, this strategy molecules. Second, the Cp ring forms van der Waals interac-
demonstrated high cell selectivity, as 75.3% of HER2-positive tions with Pim-1 through Phe49, Ile185, and the methylene
SKBR-3 tumor cells were killed, whereas only 15.5% cell death group of Glu171. Third, the short distance (3.0–3.2 Å) between
was observed in HER2-negative MCF-10A normal cells. the carbonyl oxygen atom of the CO ligand and Gly45 strongly
suggests dipolar interactions between the CO moiety and the
2.2 Enzymes and proteins positively polarised methylene and carbonyl groups of Gly45,
which are presumably due to the higher negative potential of
Enzymes hold great potential as natural targets for metal
the ruthenium carbonyl group. It is worth noting that the metal
complexes because (i) metals are able to affect the structural
centre is not directly involved in interactions with Pim-1. In
integrity and functionality of enzymes through the formation of
contrast, the metal controls the orientation of its coordination
strong covalent coordination bonds, and (ii) interfering with an
organic ligands in the receptor space, consequently generating
endogenous metal that is necessary for enzymatic action allows
three-dimensional structures that are complementary in shape
the inactivation of enzymes such as zinc–metalloenzymes.67 In
and functional group presentation to the active sites of Pim-1.70
fact, the significance of enzymes as metallodrugs’ action targets
Wee1 is a tyrosine kinase that responds to double-stranded
was initially discovered as an afterthought, during which DNA
DNA breaks and is overexpressed in many breast tumor cell
attracted more interest and attention.
lines. Recently, Wee1 has been recognised as a potential anti-
The first rationally developed organometallic complex for
tumor target for cancer treatment, especially for TP53-mutated
certain enzyme-targeting is a class of CpRu complexes reported
tumor cells. The first metal-based Wee1 inhibitor was reported
by the Meggers group in the 2000s.68,69 Complexes 2-29 and 2-
in 2018 by the Leung and Ma group.71 This rhodium(III)
30 were designed by mimicking the structural features of the
complex 2-31 (Fig. 11(a)) was identified from five similar
protein kinase inhibitor staurosporine (Fig. 10(a)), and deter-
rhodium(III) complexes through a single-site semi-quantitative
mined to be more active for glycogen synthase kinase 3 (GSK-3)
immunoassay, and exhibited a better Wee1 inhibitory property
than some well-established organic protein kinase inhibitors.
than the well-known Wee1 inhibitor MK-1775. Conjugation of
Complexes 2-29 and 2-30 also featured significantly higher
the rhodium unit and phenanthroline ligands is essential for
selectivity towards GSK-3 than other protein kinases. In addi-
this inhibitory effect. Complex 2-31 also showed greater anti-
tion, complex 2-30 was proved to be able to switch on the Wnt
tumor potency in four breast tumor cell lines compared to the
signal transduction pathway both in vitro and in vivo.69
normal liver cell line LO2, and its cytotoxicity was stronger
Encouragingly, the cocrystal structure of complex (S)-2-30 bind-
against TP53-mutated MDA-MB-231 and MDA-MB-468 cell lines
ing with Pim-1, a human serine/threonine protein kinase that is
than against TP53-wild-type MCF-7 and MCF-10A cell lines,
overexpressed in human prostate cancer cells, has been suc-
indicating the vital role of TP53 in its anti-tumor activity.71
cessfully solved to account for its great affinity (Fig. 10(b)),70
Cyclin-dependent kinases (CDKs) and cyclins are the major
from which key binding sites of the chemical structure (S)-2-30
control switches in cell cycle progression. There is evidence that
with Pim-1 are depicted. First, the pyridocarbazole unit of (S)-2-
b-carboline alkaloids can inhibit CDK activity by competitively
binding to the ATP-Mg2+ binding pocket.72,73 Inspired by this,
our group synthesised a class of Ru–arene complexes bearing
bioactive b-carboline derivatives. Among these, complex 2-32
Fig. 10 (a) Chemical structures of the protein kinase inhibitor stauros- Fig. 11 (a) Chemical structures of representative organometallic com-
porine and organo-ruthenium complexes designed as protein kinase plexes 2-31 (Wee1 targeting), 2-32 (CDK targeting), 2-33 (ASNS targeting)
inhibitors; (b) the crystal structure of Pim-1 with (S)-2-30 bound to the and 2-34 (vimentin targeting); (b) the proposed interaction mechanism of
ATP binding site (PDB: 2BZI)70 and key active binding sites. complex 2-33 with ASNS.
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(Fig. 11(a)) exhibited significant inhibitory potency against and anti-metastatic activities.77 In their previous study using
CDK1/cyclin B and 3 to 12 times higher cytotoxicity than clickable photoaffinity probes, six potential protein targets were
cisplatin in a panel of cancer cell lines, especially for the identified for an NHC–gold(III) complex that is isostructural to
cisplatin-resistant A549R cell line. Mechanistic studies indi- 2-34 through a multi-faceted approach.78 Herein, the cellular
cated that complex 2-32 can arrest cells in the G2M phase, thermal shift assay and immunoblot analysis were further
repress CDK1/cyclin B1 expression, and increase intracellular applied to determine the molecular target of 2-34 from those
reactive oxygen species (ROS) levels to induce apoptosis via a six proteins. Vimentin, a cytoskeletal intermediate filament
mitochondrial dysfunction pathway.74 In addition, we prepared protein, was identified as a cellular target. In contrast to the
another iridium(III)-b-carboline conjugation as a strong CDK covalent binding mode of 2-33 with ASNS, molecular dynamics
inhibitor, which will be discussed in Section 4.2 due to its simulation analysis indicated that 2-34 binds with vimentin via
autophagy induction ability.75 noncovalent interactions through its orthogonal scaffold syner-
The metal centre in the organometallic framework not only gistically arranged by both the [Pt(C^N^N)] plane and NHC
plays a structural role in organising the organic ligands to unit.77
facilitate binding with the protein in the three-dimensional Thioredoxin reductase (TrxR) plays crucial roles in the
space, but also directly participates in the interaction with maintenance of the cancer phenotype and intracellular redox
enzymes through covalent coordination. The Che group devel- homeostasis and is overexpressed in many aggressive
oped an effective anti-tumor NHC-platinum(II) complex 2-33 cancers.79 TrxR is particularly attractive as an anti-tumor target
(Fig. 11(a)).76 By combining thermal proteome profiling with for organometallics because its sulfur and selenium donor
MS-based multiplexed quantitative proteomics analysis, aspar- atoms favour coordination with soft Lewis acids such as
agine synthetase (ASNS) was identified as an unbiased mole- gold80,81 and rhodium.82,83 For example, Tang et al. developed
cular target of 2-33. ASNS is a glutamine aminotransferase a gold(I)–NHC complex 2-35 (Fig. 12(a)) with aggregation-
enzyme that is overexpressed in some tumor cells and plays a induced emission (AIE) property. As indicated by the covalent
vital role in tumor growth and metastasis. Treatment of NCI- docking analysis, complex 2-35 can greatly bind with TrxR
H460 cells with 2-33 led to a significant increase in ASNS through the direct interaction between the gold center and
thermal stability by B2 1C, whereas the melting temperature Cys498 of the human TrxR accompanied with other noncova-
of glyceraldehyde-3-phosphate dehydrogenase remained lent interactions (Fig. 12(b)).84 Due to its TrxR targeting ability,
unchanged. Quantitative analysis of multiple reaction monitor- complex 2-35 is able to produce significant intracellular ROS
ing revealed that intracellular asparagine levels decreased by and efficiently intervene in redox homeostasis inside tumor
approximately 50% after 5 h of incubation with 2-33. In addi- cells, therefore demonstrating strong anti-tumor activity and
tion, treatment with this complex under asparagine- and good selectivity to tumor cells over healthy cells. The Liu group
glutamine-deficient conditions led to a significant decrease in recently reported a gold(I)-acetylide complex 2-36 that can
cell viability, which could be reversed by exogenous asparagine efficiently trigger cancer cell apoptosis through TrxR inhibition
supplementation. The interaction of complex 2-33 with ASNS (Fig. 12(a)).85 Compared with the pure oleanolic acid ligand
was further revealed to involve covalent coordination between which is not active on TrxR, complex 2-36 displayed much
the active bis-NHC–platinum(II) species transferred from the higher TrxR inhibition activity, highlighting the importance of
hydrolysis of complex 2-33 and Cys residues of ASNS the gold(I) centre in the TrxR-inhibitory effect. Correspond-
(Fig. 11(b)). Owing to its ASNS targeting ability, complex 2-33 ingly, complex 2-36 was more cytotoxic to ovarian cancer cells
exhibited similar in vitro anti-tumor activity and less in vivo side than the oleanolic acid ligand. Molecular docking analysis
toxicity relative to cisplatin by limiting the availability of also suggested that complex 2-36 features potential direct
asparagine.76 binding with TrxR.85 Very recently, taking advantage of the
The same group recently reported another NHC-platinum(II) polarisation effect of the selenium atom, the Chen and Ma
complex 2-34 featuring a distinct orthogonal structure group rationally constructed a ruthenium coordination
(Fig. 11(a)) with highly efficient in vitro and in vivo anti-tumor complex with an electrophilic centre –N–Se(d+)–N–. Through
Fig. 12 (a) Chemical structures of representative organometallic complexes 2-35–2-36 (TrxR targeting) and 2-37 (KDM5A targeting); (b) the schematic
illustration of key binding sites between complex 2-35 and human TrxR predicted by docking analysis.
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such a noncovalent TrxR targeting strategy, this complex spe- (Fig. 13(a)). Docking studies revealed that the interaction of
cifically interacts with the SeC residues in the redox active motif JAHA with HDAC8 generally resembles the interaction mode
of TrxR at the 498 site.86 between this enzyme and SAHA, and its ferrocenyl group is
Lysine-specific demethylase 5A (KDM5A) is overexpressed in comfortably accommodated in a shallow pocket of HDAC8,
a number of cancer cells and facilitates tumorigenesis, metas- which is reported to be malleable and adaptable to different
tasis and drug resistance.87 Leung and coworkers developed a structures of ligands. As a result, JAHA demonstrated similar
rhodium(II) complex 2-37 (Fig. 12(a)) as a potent inhibitor of inhibitory activities on class I HDACs relative to SAHA.92
KDM5A.88 Through a chemiluminescence assay, 2-37 was iden- Although JAHA displayed slightly weaker cytotoxicity than
tified from six compounds as a KDM5A inhibitor due to its SAHA, the ferrocenyl motif endows JAHA with more diversified
higher activity than CPI-455 (the reported KDM5A inhibitor) action modes related to antioxidant activity and DNA repair,
and selectivity to KDM5A compared with KDM1A, KDM4A and probably due to its potential for redox activity and induction
KDM6B. As a result, 2-37 can suppress the interaction between of ROS.93 Recently, Hartinger and coworkers developed a
KDM5A and H3K4me3/2, resulting in H3K4me3/2 accumula- Cp*Rh complex 2-38 functionalized with a SAHA analogue
tion and p27-gene activation, efficiently leading to cell cycle (Fig. 13(a)).94 Although complex 2-38 is slightly less cytotoxic
arrest and cell death. This complex also significantly represses than SAHA, its HDAC inhibition activity is indeed up to 30-fold
tumor xenograft growth in vivo with much lower toxicity than higher than that of SAHA, especially for HDAC6. In vivo experi-
both cisplatin and doxorubicin.88 ments using the zebrafish model demonstrated higher anti-
Synergistic effects of the metal centre and its functional angiogenic activity of complex 2-38 compared to that of its
ligand(s) are preferable for anti-tumor organometallics to SAHA derivative ligand, highlighting the importance of the
improve anti-tumor efficacy. Inspired by this, functionalization metal centre in bioactivity.94 Our group designed a Re(I)-SAHA
of organometallics with certain enzyme inhibitors has recently conjugation 2-39 (Fig. 13(a)) with both mitochondria and HDAC
become a burgeoning drug design strategy for this purpose. targeting, which showed a 2.5-fold greater cytotoxicity against
Histone deacetylases (HDACs) are enzymatic epigenetic HeLa cells and a slightly lower inhibitory activity on HDACs
modulators that are overexpressed in solid tumor-malig- compared with SAHA.95 Other than SAHA, valproic acid is also a
nancies and haematological cancers. By catalysing the removal well-known HDAC inhibitor that can be functionalized with
of acetyl groups from DNA-binding histones, HDACs are organometallics. For example, our group prepared phosphor-
responsible for the regulation of expression and activity of escent iridium(III) complexes 2-40–2-42 featuring valproic acid
many non-histone proteins in cancer initiation and as a potential HDAC inhibitor (Fig. 13(a)).96 These complexes
progression.89 Targeting HDACs is a promising strategy for feature similar HDAC inhibitory activity relative to valproic acid
anti-tumor small molecules, validated by the clinical success and are up to 90-fold more cytotoxic to A549R cells than
of the FDA approval HDAC inhibitors romidepsin (FK-228) and cisplatin.
suberoylanilide hydroxamic acid (SAHA) (Fig. 13(a)).90 The Glutathione S-transferases (GSTs) are a family of antioxidant
binding mode of SAHA with human HDAC8 was determined and detoxifying enzymes. GSTs are responsible for catalysing
by the crystal structure. As shown in Fig. 13(b), SAHA mainly the conjugation of glutathione to various endogenous and
binds with Zn2+ in the active site of HDAC8 via its hydroxamate, exogenous electrophilic substrates, thus accelerating anti-
and its amide group forms a hydrogen bond with Asp101 tumor agent degradation and reducing their intracellular
of HDAC8 to further strengthen their interaction.91 In terms availability.97 Upregulation of GSTs is a frequent feature for a
of organometallics, Jay Amin hydroxamic acid (JAHA) has been variety of human cancer cells and is always accompanied by
synthesized as a ferrocene-containing analogue of SAHA drug resistance, making GSTs an attractive anti-tumor target to
Fig. 13 (a) Chemical structures of representative organometallic HDAC inhibitors; (b) the binding mode of human HDAC8 and SAHA determined by
crystal structure (PDB: 1t69).91
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Fig. 14 (a) Chemical structures of representative organometallic GST inhibitors; (b) the interactions between GST P1-1 and the Ru–arene moiety of
complex 2-43 determined by crystal structure (PDB: 3DD3).98
increase drug efficacy.13,97 For example, by using a GST inhi- Non-steroidal anti-inflammatory drugs (NSAIDs) such as
bitor, ethacrynic acid (EA), the Dyson group has constructed a naproxen, dichlofenac, ibuprofen, and aspirin have been
ruthenium(II)-EA conjugation 2-43 (Fig. 14(a)) as a superior GST reported to be active on tumor cells via targeting cyclooxy-
Pi class (GST P1-1) inhibitor. Importantly, the crystal structure genases (COX), which are often overexpressed in tumor
of the complex of GST P1-1 and 2-43 has been obtained.98 As cells and are correlated with drug resistance. By conjugating
illustrated in Fig. 14(b), complex 2-43 is located at the dimer different NSAIDs with a ruthenium(II)-arene moiety, the
interface and its ruthenium centre coordinates with two thiol Mukhopadhyay group prepared Ru-NSAID complexes 2-53–2-
groups of Cys101 from each chain through chloride ligand 56 (Fig. 15(a)).101 After complexation, all the metal complexes
displacement. Other noncovalent contacts from both organo- demonstrated stronger inhibition of COX and cytotoxicity than
ruthenium and EA moieties to GST P1-1 such as hydrogen their corresponding NSAIDs. Docking analysis of complex 2-54
bonds, van der Waals interactions, and p–p stacking are also and COX-2 revealed that besides interactions between COX-2
involved, synergistically resulting in the specific recognition of and dichlofenac, this organometallic complex features addi-
GST P1-1 by complex 2-43. Furthermore, the same group tional halogen bonding interactions from other ligands
rationally synthesised another generation of ruthenium(II)- (Fig. 15(b)), showing greater binding ability with COX-2 than
and osmium(II)-EA conjugations 2-44–2-49 with different metal the sole dichlofenac. Later on, a single cyclo-metalated
to EA ratios to study the influence of the metal centre and ruthenium(II) complex 2-57 containing both ibuprofen and
metal-to-inhibitor ratio on their anti-tumor activities naproxen moieties was generated (Fig. 15(a)).102 This complex
(Fig. 14(a)).99 Among these, complexes 2-46 and 2-47 with a showed a stronger inhibition ability towards COX-2 than free
1 : 2 metal to EA ratio were the most active, especially against ibuprofen and naproxen ligands, and the cytotoxicity and
the cisplatin-resistant A2780cisR cell line. selectivity index of complex 2-57 were superior to those of
The Sun group reported a class of GST-targeting cisplatin.
ruthenium(II)–arene complexes 2-50–2-52 functionalized with Poly(ADP-ribose) polymerase 1 (PARP-1) is one of the most
another widely applied GST inhibitor, 6-(7-nitro-2,1,3- abundant non-histone nuclear proteins pivotal for DNA replica-
benzoxadiazol-4-ylthio)hexanol (NBDHEX) (Fig. 14(a)).100 These tion, transcriptional regulation and DNA damage repair. It is
complexes displayed greater improvement in cytotoxicity also known that the upregulation of PARP-1 is often related to
in a panel of tumor cell lines in vitro than either the non- drug resistance, making this enzyme a promising anti-tumor
NBDHEX-functionalized ruthenium(II) complex or the NBDHEX target. The Zhu group reported a ruthenium(II)-arene complex
derivative ligand alone, highlighting that such conjugations 2-58 featuring 3-aza-5[H]-phenanthridin-6-one (APO), a new
feature a positive synergistic effect on tumor cells. Both generation of PARP inhibitor (Fig. 16(a)).103 Direct coordination
their GST inhibition ability and cytotoxicity followed similar with the ruthenium moiety greatly improved the cytotoxicity of
trends of 2-52 4 2-51 E 2-50. The increasing number of alkyl APO by up to 3.2-fold, and the in vitro PARP-1 inhibitory activity
groups provides a higher electron density at the Ru centre, was even stronger than that of some clinical PARP-1 inhibitors.
thereby accelerating hydrolysis and facilitating biological Further mechanistic studies verified the synergistic effects of
activities. both components in complex 2-58: the ruthenium–arene unit
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Fig. 15 (a) Chemical structures of representative organo-ruthenium COX inhibitors; (b) the schematic illustration of key binding sites between complex
2-54 and COX-2 predicted by docking analysis.
was able to strongly bind to DNA to intervene in transcription, for targeted anti-tumor metallodrug construction.106–111 For
while APO facilitated this complex to inhibit the catalytic instance, our group developed rhenium(I) tricarbonyl complex
activity of PARP-1 to disturb DNA repair, finally leading to cell 2-60 that is functionalized with a terthiophene group for
death.103 A similar concept has recently been applied by photodynamic therapy (PDT) and a benzene sulfonamide for
Grgurić-Šipka and coworkers, who conjugated a class of CA IX inhibition (Fig. 16(a)).109 Molecular docking analysis
ruthenium(II)-arene complexes with derivatives of another between complex 2-60 and CA IX revealed that the benzene
PARP-1 inhibitor, 3-aminobenzamide (3-AB).104 Among these, sulfonamide group of complex 2-60 can coordinate with the
complex 2-59 (Fig. 16(a)) exhibited better PARP-1 inhibitory active central Zn2+ of CA IX and features some hydrogen
activity than 3-AB, but demonstrated no cytotoxicity towards bonding interactions, while the terthiophene moiety is stuck
several tumor cell lines, presumably due to its very low cell outside the binding pocket of CA IX. As a result, complex 2-60
uptake efficiency. anchored on the cell membrane through binding with CA IX,
Carbonic anhydrase IX (CA IX) is a tumor-overexpressing leading to the inactivation of HIF-1a to overcome tumor
transmembrane protein that plays key roles in cellular pH hypoxia.109 Mukherjee and coworkers generated a series of
regulation. As a zinc metalloenzyme, CA IX can be efficiently sulfonamide ruthenium(II)-arene complexes, in which com-
inhibited by compounds with a zinc binding group such as plexes 2-61 and 2-62 (Fig. 16(a)) were cytotoxic to MDA-MB-
sulfonamides, as illustrated by the crystal structure in 231 and MIA PaCa-2 tumor cell lines, while not active in
Fig. 16(b).105 Therefore, benzene sulfonamides are a well- Chinese hamster ovary (CHO) and Madin-Darby canine kidney
known class of CA inhibitors and have been recently applied (MDCK) normal cells.106 Encouragingly, their activity on MDA-
Fig. 16 (a) Chemical structures of representative organometallic complexes 2-58–2-59 (PARP-1 targeting), 2-60–2-62 (CA IX targeting) and 2-63–2-65
(HIF-1a targeting); (b) the key binding mode between human CA IX-mimic and a benzene sulfonamide derivative determined by crystal structure (PDB:
5JMZ).105
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MB-231 cells was enhanced under hypoxia, which is an impor-

tant hallmark of cancer progression. Considering the higher
expression levels of CA IX in hypoxia than in normoxia, this
result strongly suggests that CA IX inhibition significantly
influences their anti-tumor property.
The hypoxic tumor microenvironment is usually associated
with drug resistance and poor patient prognosis, in which
hypoxia-inducible factor-1a (HIF-1a) plays an essential role.

Due to intratumoral hypoxia and genetic alterations, HIF-1a
is selectively overexpressed in many cancer cells but shows no
expression in corresponding healthy tissues.112 Xu and Gou
et al. developed a series of ruthenium(II) arene complexes 2-63–
2-65 functionalized with an efficient HIF-1a inhibitor, YC-1 Fig. 17 (a) Chemical structures of G4-targeted organometallic com-
(Fig. 16(a)).113 Owing to the specific inhibitory ability of the plexes; (b) the solution NMR structure of the 2-66/VEGF-G4 binding
YC-1 moiety, complexes 2-63–2-65 featured higher anti-tumor adduct (PDB: 6LNZ) (adapted with permission from ref. 120. Copyright
activity under hypoxic conditions than under normoxia in a 2021 Wiley-VCH); (c) the crystal structure of the adduct of complex 2-67
and Tel 23-G4 (PDB: 5CCW).123
panel of tumor cell lines, and showed much less toxicity than
cisplatin to human umbilical vein endothelial cells. The cyto-
toxicity of these complexes was positively correlated with their imaging microscopy (FLIM), the specific binding ability of 2-66
hydrolysis rates and cellular accumulation, with a general trend with G4s was demonstrated in living cells. Owing to this G4
of 2-65 4 2-64 4 2-63. Western blot analysis confirmed that all targeting ability, complex 2-66 showed better cytotoxicity than
of these complexes, as well as the YC-1 containing ligand, cisplatin towards a panel of tumor cell lines and strongly
efficiently suppressed HIF-1a protein expression in a dose- repressed VEGF expression and blood vessel growth in the
dependent manner. Therefore, YC-1 conjugation endows these zebrafish model.120
organometallics with tumor hypoxia-targeting ability, thus The Casini group developed a gold(I)-carbene caffeine
improving their anti-tumor activity and selectivity.113 complex 2-67 that is highly cytotoxic against a panel of tumor
2.3 G-quadruplex DNA (G4 DNA) cell lines, behaving as a selective G4 stabiliser (Fig. 17(a)).121–123
Importantly, the crystals of 2-67 and Tel 23-G4 adducts were
G-quadruplex DNA (G4 DNA) refers to the four-stranded struc- grown and solved by X-ray diffraction. As illustrated in
tures formed in guanine-rich nucleic acid sequences via p–p Fig. 17(c), one Tel 23-G4 can noncovalently bind to three
stacking of the G-tetrad, a planar structure containing four gold–carbene units at two distinct sites while maintaining a
guanines linked together by Hoogsteen hydrogen bonds.114 In characteristic propeller conformation. Only one caffeine mole-
recent years, G4s have gained increasing attention as a cule in each complex 2-67 interacts with guanine residues,
potential anti-tumor target because (1) G4 formation within while the other caffeine moiety protrudes outside the tetrad
the telomeric DNA 3 0 -overhang is able to repress telomerase surface.123 Based on this crystal structure, the binding mecha-
activity, which is mutated in normal tissues but overexpressed nism and free energy landscape of complex 2-67 with G4s were
in most cancer cells. As a result, the formation of G4s can further studied by metadynamics, providing a useful approach
remarkably shorten telomeres and suppress proliferation and for the rational design of G4-targeted anti-tumor drugs.124
immortalisation of tumor cells. (2) Intramolecular G4 struc-
tures produced in oncogene promoter regions can disturb
oncogene transcription and expression.115 2.4 Transfer RNA (tRNA)
During the past few years, our group has been working on In recent years, accumulating evidence has revealed the crucial
the development of G4-targeted platinum(II) complexes.116–119 roles of RNA in many human diseases including cancers,
For example, an NHC-Pt complex 2-66 was synthesized and making RNA a promising therapeutic target for small molecule
studied for its interaction with G4s (Fig. 17(a)).120 Interestingly, drug development.125,126 Among all forms of RNA, tRNA has
upon treatment with promoter G4s, this electronically neutral been unveiled to be upregulated in highly metastatic breast
and spatially non-planar complex 2-66 experienced an unpre- cancer cells.127,128 tRNA stands for a class of small conserved
cedented structural transformation to a positively charged RNAs and is responsible for the genetic code translation from
intermediate through chloride hydrolysis and then to a planar messenger RNA (mRNA) and the delivery of corresponding
complex via NHC rotation and pyridine coordination. Complex amino acids to the polypeptide chain.129 In 2019, the Arjmand
2-66 displayed high selectivity for G4s over double-stranded and group serendipitously discovered that a series of copper(II)-
single-stranded DNA. The resolved solution NMR structure of Schiff base coordination complexes could preferentially bind
the 2-66/VEGF-G4 binding adduct revealed that after structural tRNA as compared to calf thymus DNA (ct-DNA).130 Later, this
transformation, flat 2-66 matches the 3 0 -G-tetrad of VEGF-G4 group further synthesised an organotin(IV) and a ruthenium(II)-
and induces loop rearrangement of VEGF-G4 to generate the arene complex 2-68 and 2-69 based on Schiff base ligands
most stable structure (Fig. 17(b)). Using fluorescence lifetime (Fig. 18(a)). Binding interactions of these complexes with
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targeting complexes is possibly because tumor cells need more

tRNA to satisfy their rapid proliferation.
In general, as summarized in Table 1, either the inherent
properties of the metal center or functional ligands, and in
some cases both of them, endow organometallics with certain
biomolecule-targeting ability and tumor selectivity. At present,
the combination of a metal-based framework with a bioactive
Fig. 18 (a) Chemical structures of tRNA-targeted organometallic com-

group such as biomolecules and clinical drugs/inhibitors is a
plexes; (b) molecular docking of complex 2-68 bound to tRNA (adapted
with permission from ref. 131. Copyright 2020 American Chemical popular strategy to realise targeted organometallics, and syner-
Society). gistic effects are always favourable for drug development.
3. Anti-tumor organometallics
ct-DNA and tRNA were investigated by optical and electroche-
mical techniques, which demonstrated that complexes 2-68
perturbing tumor homeostasis
and 2-69 feature a stronger binding ability and a lower binding As biomolecule interactions further affect the balance between
energy with tRNA than with ct-DNA.131 As shown in Fig. 18(b), cellular material networks and the tumor microenvironment,
computational density functional theory (DFT) studies indi- this section focuses on tumor homeostasis perturbation caused
cated that the highly exposed base pairs and extraordinary by organometallics. Homeostasis is a dynamic state controlled
bulge region of tRNA facilitated the interactions of these by organisms to maintain an internal balance and adapt to
organometallic complexes with tRNA. In addition, the aromatic external stimulations, and functions as a key process in tumor
units of 2-68 and p-cymene alkyl groups of 2-69 lead to hydro- initiation and development.132 Tumor is a multi-step biopro-
phobic interactions with tRNA surfaces, and their binding cess in which normal cells first suffer a negative initiating
affinity can be further stabilised through hydrogen bonds stimulation and subsequently a second stimulation accompa-
between the hydroxy group(s) in these organometallic com- nied by aberrant dynamic regulation. The homeostasis of
plexes and RNA bases. Complexes 2-68 and 2-69 showed potent tumorigenesis mainly includes high energy supply, tolerant
activity towards Huh7 and Du145 tumor cell lines and were radical scavenging, abnormal metal distribution, and dysfunc-
nontoxic to PNT 2 healthy cells.131 The good selectivity towards tional immune surveillance, thereby resulting in rapid prolif-
tumor cell lines over normal ones demonstrated by these tRNA eration and facile spread of malignant cells. First, metabolic
Table 1 Examples of selected biomolecular targets and the corresponding anti-tumor organometallic compounds
Biomolecular target Organometallic type Metal Bio-functional group Ref.

Biotin receptors, SMVT Metal arene, metal Cp Ru Biotin 29–32
Glucosyl receptors and Cyclo-metalated complex, metal acetylide Pt, Au Glucose, galactose 35–37
GLUTs
MOR, DOR Metal arene, metal Cp Rh GPCR peptide 39
GRPR Cyclo-metalated complex Ir JMV594 peptide 40
Integrin Cyclo-metalated complex Pt RGD peptide 42 and 43
Estrogen receptor Metal arene, metal Cp Ti, Fe, Ru, Tamoxifen, anastrozole 44,47–49 and
Re 52
EGFR Metal arene, cyclo-metalated complex Ru, Pt Tyrphostin, gefitinib, 4- 56
anilinoquinazoline
PTK7 Metal carbene Au Sgc8c aptamer 58
HER2 Metal carbene, metal Cp Au, Ru Trastuzumab, HER2-affibody 64–66
GSK-3 Metal carbonyl, metal Cp Ru — 69
Wee1 Cyclo-metalated complex Rh — 71
CDK Metal arene, cyclo-metalated complex Ru, Ir b-Carboline 74 and 75
Asparagine synthetase Metal carbene Pt — 76
Vimentin Metal carbene Pt — 77
TrxR Metal acetylide, metal carbene Au, Rh — 84 and 85
KDM5A Cyclo-metalated complex Rh — 88
HDAC Metal Cp, metal carbonyl, cyclo-metalated Fe, Rh, Ir SAHA, valproic acid 92 and 94–96
complex
GST Metal arene Ru, Os EA, NBDHEX 98–100
COX Metal arene, cyclo-metalated complex Ru Ibuprofen, naproxen, aspirin, 101 and 102
dichlofenac
PARP-1 Metal arene Ru APO, 3AB 103 and 104
CA IX Metal arene, metal carbonyl Re, Ru, Os Sulfonamide 106 and 109
HIF-1a Metal arene Ru YC-1 113
G4 DNA Metal carbene Pt, Au — 120 and 121
tRNA Metal arene Sn, Ru — 131
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Fig. 19 Tumor homeostasis perturbation caused by organometallics. In energy homeostasis, organometallics can inhibit glucose metabolism and
switch the respiration mode from aerobic glycolysis to OXPHOS, and directly block ATP and metabolic intermediate production in these two pathways; in
redox homeostasis, organometallics can elevate reductive stress or oxidative stress by transferring protons or electrons, resulting in imbalance of cellular
redox potential; in metal homeostasis, organometallics can capture ions in the cellular labile metal pool and redistribute them in organelles, and further
affect metalloproteins, or participate in catalysis to alter the valence state of metal ions; in immune homeostasis, organometallics can turn ‘‘cold’’ tumor
into ‘‘hot’’ tumor by improving immuno-active cell infiltration in the tumor core and inhibiting immunosuppressive cells. All of these homeostasis
perturbations ultimately promote tumor cell death progression. TCA cycle: tricarboxylic acid cycle; OXPHOS: oxidative phosphorylation; ATP: adenosine
triphosphate; NADH: nicotinamide adenine dinucleotide; GSH: glutathione; ROS/RNS: reactive oxygen/nitrogen species.
disorders endow malignant tumors with hypoxic conditions (OXPHOS).133 This so-called ‘‘Warburg effect’’ has affected and
and render them resistant to conventional anti-cancer therapy. guided the investigation of anti-tumor treatment for genera-
An imbalanced redox state induces mutations in oncogenes tions. In normal tissues, cells first metabolise glucose to
and the miscoding of normal genes that are associated pyruvate via glycolysis and then entirely oxidise a large propor-
with tumor tolerance. In addition, excess endogenous metals tion of pyruvate to CO2 in the mitochondria during OXPHOS to
promote nutrient uptake and elevate cellular stress which maximise ATP production and minimise lactate levels. Under
could benefit to tumor growth. Finally, insufficient infiltration hypoxic conditions, normal cells redirect the metabolic path-
of lymphocytes in the tumor core and overexpression of way by maximising lactate production away from mitochondrial
immune checkpoints on the tumor surface lead to failure of OXPHOS.134 In contrast, most tumor cells directly convert
immunosurveillance. glucose to lactate, regardless of the oxygen content. Such
Thus, to improve drug efficacy, it is desirable to develop anti- alterations in tumor metabolism enable tumor cells to escape
tumor agents that can act by perturbing tumor homeostasis to from normal apoptosis and immune defense, and are signifi-
achieve multiple and complex action mechanisms: (i) distur- cant for oncogene revolution, tumorigenesis, tumor prolifera-
bance of tumor intracellular energy homeostasis by modulating tion and metastasis.135
aerobic glycolysis and OXPHOS; (ii) hindrance of redox home- Based on the relationship between altered metabolism and
ostasis by interrupting GSH/ROS/NADH-mediated signalling tumor development, promoting metabolic reversion from aero-
pathways; (iii) alteration of metal homeostasis essential for bic glycolysis to OXPHOS has the potential to inhibit tumor
physiological processes by rearranging certain metal ions and growth. Dichloroacetate (DCA) is a metabolic drug that reverses
regulating metalloproteins; (iv) deployment of the immune glycolytic metabolism in tumors and restores mitochondrial
system by altering inflammation and recruiting lethal types of function by inhibiting the activity of pyruvate dehydrogenase
immune cells to inhibit the functions of immunosuppressive kinase (PDK), resulting in the conversion of pyruvate to acetyl-
cells (Fig. 19). Recent progress in homeostasis-regulated anti- CoA.136,137 However, the lack of mitochondrial accumulation of
tumor organometallics based on biological balance is pre- DCA restricts its bioavailability for metabolic reversion. In this
sented in this section. regard, our group synthesised Re(I) carbonyl complex 3-1 con-
jugated with a DCA-modified hydrophobic ligand to promote
3.1 Energy homeostasis metabolic reversion (Fig. 20(a)).138 After metallic modification,
In the 1920s, Warburg found that tumor cells prefer to generate 3-1 reserved the PDK-inhibitory capacity of DCA and completely
adenosine triphosphate (ATP) by aerobic glycolysis, which is a reversed the metabolic mode from glycolysis to OXPHOS in
less efficient pathway compared to oxidative phosphorylation PDK highly expressing NCI-H1229 cells (Fig. 20(b)), and the
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iridium(III) complex 3-3 that can efficiently disturb tumor cell

metabolism (Fig. 21(a)).142 The reactive chloromethyl subunits
of 3-3 immobilized itself in mitochondrial proteins due to
nucleophilic substitution with reactive thiols. Thus, this
iridium(III) complex attenuates mitochondrial bioenergetic
function by inhibiting mitochondrial respiration with highly
selective cytotoxicity in human lung carcinoma cells. After 3-3
treatment, the mitochondrion-encoded subunits I, II, and III of

cytochrome c oxidase in the ETC were remarkably downregu-
lated, resulting in ATP reduction, respiration inhibition, proton
leakage, and mitochondrial depolarisation. As an inhibitor of
ATP, complex 3-3 further induced many important anti-cancer
processes, such as DNA damage response, cell cycle arrest, and
apoptosis.
Considering the complexity of tumor metabolism, new
therapies that can simultaneously perturb aerobic glycolysis
Fig. 20 (a) Chemical structures of organometallic complexes 3-1 and 3-2 and mitochondrial bioenergetics have been investigated.
converting energetic metabolism; (b) illustration of metabolic reversion
from aerobic glycolysis to OXPHOS induced by representative complexes
Because chromosomal instability (CIN) induced by aneuploidy
3-1 and 3-2. is closely related to the tumorigenesis of colorectal cancer,143
Ott et al. designed a xanthine-derived multitarget alkynyl gold(I)
complex 3-4 for aneuploidy-tolerant colorectal cancer treatment
involved O2 consumption was visualised by FLIM imaging. This (Fig. 21(b)).144 A mechanistic study demonstrated that this
complex depolarises the mitochondrial membrane potential gold(I) complex could inhibit TrxR and mitochondrial respira-
(MMP) and inhibits mitochondrial bioenergetics, resulting tion, resulting in p53 and ROS activation with mitochondrial
in the inhibition of metastasis, invasiveness, and angiogenesis. damage. Subsequently, complex 3-4 exhibited superior anti-
Finally, complex 3-1 exhibited excellent anti-tumor properties cancer properties through aneuploid-induced CIN. This was
with few side effects in vivo, indicating the potential of due to ATP reduction as a result of mitochondrial respiration,
metabolism-targeted organometallic agents. glycolysis downregulation, and Akt1 activation. Simultaneously,
Moreover, Sadler et al. designed a stable organometallic ERK1/2 activation also contributed to 3-4-mediated cytotoxicity.
half-sandwich Os(II) arene complex 3-2 as a metabolic switch These results highlight that the combination of aneuploidy
for cancer treatment (Fig. 20(a)).139 After complex 3-2 treat- induction and tumor metabolism could serve as a useful
ment, three missense mutations coding for ND5, a subunit of strategy for anti-tumor organometallics development.
complex I in the electron transport chain (ETC), were found in Su and co-workers also reported a rhein-modified
the mitochondrial genome (Fig. 20(b)). Time-series RNA mitochondria-targeting cyclo-metalated iridium(III) complex 3-
sequencing showed that 3-2-treated epithelial ovarian cancer 5 with the potential to inhibit metabolic adaptations
cells underwent metabolic reversion from aerobic glycolysis to (Fig. 21(c)).145 The cellular ROS level was elevated approxi-
OXPHOS, which was associated with the above-mentioned mately 26-fold and the ultrastructure of mitochondria was
mutations in complex I. Furthermore, this compound elevated destroyed upon 3-5 treatment. Meanwhile, mitophagy was
mitochondrial ROS levels and impaired cellular response to induced by this iridium(III) complex with light chain protein
excessive ROS with downregulated antioxidant proteins, result- 3B activation through the phosphatidylinositol 3-kinase signal-
ing in DNA damage with upregulation of ATM, TP53, and p21 ling pathways. Importantly, alteration of the oxygen consump-
proteins. A cell death mechanism study showed that 3-2 could tion rate and extracellular acidification rate after 3-5
lead to the initiation of apoptosis signalling but not translate to treatment indicated the suppression of both OXPHOS and
the expression of effector caspases in a mode regulated by both glycolysis, resulting in sharp ATP depletion and eventual star-
pro- and anti-apoptotic proteins, which is different from cis- vation death in A549 cells. Complex 3-5 was also extremely
platin. These results indicate that converting the tumor meta- active in cisplatin-resistant A549R cells and 3D multicellular
bolic mode is a feasible strategy to improve organometallics tumor spheroids, as it upregulated the cisplatin-imported
anti-tumor efficacy. protein CTR1 while downregulated the cisplatin-exported
In addition to aerobic glycolysis, mitochondrial metabolism protein MRP2.
is also a symbolic hallmark of tumorigenesis.140 Based on Considering the significance of mitochondria in energy
the fact that mitochondria have well-recognised roles in bio- metabolism, mitochondrial DNA (mtDNA) is a promising can-
energetics and macromolecule biosynthesis, and that high didate for metabolic regulation. Additionally, unlike nuclear
levels of mitochondrial ROS could invoke genetic instability, DNA (nDNA), mtDNA does not feature histone protection and
hindering mitochondrial metabolism is a potential strategy nucleic excision repair mechanisms, thus making it more
for cancer treatment.141 Considering this, our group reported sensitive to destruction.146 Our group rationally designed a
a mitochondria-immobilised phosphorescent cyclo-metalated cyclo-metalated iridium(III) complex 3-6 with an extended
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Fig. 21 (a) Chemical structure of organometallic complex 3-3 intervening in mitochondrial respiration; (b and c) chemical structures of organometallic
complexes 3-4 and 3-5 simultaneously interfering with mitochondrial respiration and glycolysis; (d) chemical structures of organometallic complexes
3-6 and 3-7 disturbing energy metabolism by mtDNA damage; (e) scheme of ATP restraint in two pathways (mitochondrial respiration and glycolysis)
induced by complexes 3-3–3-7.
diimine planar ligand to facilitate its binding with mtDNA remarkable synergistic regulation of both mitochondrial and
(Fig. 21(d)).147 Considering its high lipophilicity, this complex glycolytic bioenergetics to enhance cytotoxicity in cisplatin-
was able to enrich in mitochondria based on the ICP-MS resistant cancer cells (Fig. 21(e)). These organometallics not
results. Simultaneously, 3-6 was intercalated into mtDNA by only enrich in certain sub-organelles, but also interact with
its dipyrido[3,2-a:2 0 ,3 0 -c]phenazine ligand, which was con- specific bio-macromolecules. This dual-targeting approach can
firmed by the fluorescence quenching of the cellular dsDNA be called as the cascade targeting strategy, which could pro-
sensor PicoGreen. Furthermore, it leads to mtDNA oxidative mote the molecular target identification and mechanism inves-
damage, reduced mtDNA copy number, and inhibition of tigation for anti-tumor organometallic agents.
mtDNA transcription. Importantly, complex 3-6 selectively Glucose homeostasis is vitally important in both OXPHOS
reduced the amplification efficiency of mtDNA instead of and glycolysis, and is closely related to the expression of 5 0 -
nDNA, thus demonstrating the mtDNA targeting ability of 3-6. adenosine monophosphate-activated protein kinase (AMPK)
Consequently, complex 3-6 featured remarkable cytotoxicity and insulin secretion. Metformin is a first-line drug for Type II
against a variety of tumor cell lines. It is worth noting that diabetes149 with the potential to reduce cancer incidence
when treated with an mtDNA-deficient HeLa-p0 cell line, cyto- through alteration of glucose metabolism associated with ATP
toxicity consistently decreased by B9-fold, further confirming production.150 To increase the penetrability of metformin, Ang
the importance of mtDNA in its anti-tumor activity. In addition, et al. designed an organometallic Au(III)-metformin prodrug 3-8
a detailed anti-tumor mechanism study illustrated that by for metabolic disordered triple-negative breast cancer (TNBC)
targeting mtDNA, complex 3-6 induced mitochondrial dysfunc- treatment (Fig. 22(a)).151 Complex 3-8 can quickly release
tion including a decrease in MMP, ATP depletion, respiration metformin with ligand substitution rather than reduction of
repression, and metabolic intervention, subsequently leading Au(III) to Au(I) in the presence of glutathione (GSH), which is
to simultaneous apoptosis and cytoprotective mitophagy. More- abundant in tumor cells, and demonstrated 6000-fold greater
over, in vivo studies have demonstrated that 3-6 can inhibit cytotoxicity compared to uncoordinated metformin. After 3-8
tumor growth comparably to cisplatin, while possessing low treatment, TNBC cells were found to be metabolically disor-
toxicity. Chao et al. proposed a hetero-binuclear Ir(III)–Pt(II) dered due to mitochondrial TrxR inhibition, AMPK phosphor-
complex 3-7 for pushing the tumor into a hypometabolic state ylation, and mTOR dephosphorylation, affecting kinases in the
(Fig. 21(d)).148 Lipophilic complex 3-7 could quickly penetrate glucose transport process (Fig. 22(b)). When exposed to low
the cancer cell membrane and accumulate in the mitochondria doses of complex 3-8, cells exhibited self-defense by glycolysis
to a great extent. Moreover, due to the existence of the dichloro- upregulation, unfolded protein response and mitophagy. How-
Pt(II) moiety, which is a common group that binds DNA, ever, upon relatively high-dose treatments, these defense pro-
cytotoxic complex 3-7 preferentially damaged mtDNA by mito- cesses were abrogated by impaired OXPHOS and autophagic
chondrial superoxide, which was proven by the 3-7-induced flux. Eventually, prodrug 3-8 increased lymphohistiocytic tumor
selective inhibition of mtDNA amplification. As a result, infiltration and remarkably inhibited the growth of both pri-
complex 3-7 suppressed mitochondrial respiration, protonic mary and metastatic tumors with high selectivity in vivo. In
leakage, and ATP production accompanied by glycolytic excita- addition, Liang et al. proposed a synergistic therapeutic strat-
tion, indicating that the hypometabolic state of cancer cells is egy using metformin and arene–osmium(II) complex with the
harmful for cell development. Thus, complex 3-7 exerted oxoglaucine derivative 3-9 (Fig. 22(a)).152 The osmium complex
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Fig. 22 (a) Chemical structures of organometallic complexes 3-8 and 3-9

intervening in glucose metabolism; (b) induction of glucose metabolism
reprogramming by complexes 3-8 and 3-9 via glucose transport inhibition
and glycolysis-related enzymes’ disturbance.
induced glucose metabolism reprogramming under low glu-

cose conditions by affecting the expression of glycolysis-related
genes and enzymes, including hexokinase-2, pyruvate kinase Fig. 23 (a) Chemical structures of organometallic complexes 3-10 and
isozyme type M2, lactate dehydrogenase A, and pyruvate dehy- 3-11 and their intermediates inducing oxidative stress; (b) reaction pathways
drogenase, leading to decreased intracellular pH and elevated for NADH oxidation and H2O2 production mediated by 3-10 and 3-11.
lactate levels (Fig. 22(b)). Furthermore, combined with metfor-
min, 3-9 showed an enhanced reduction in ATP levels, induc-
tion of early apoptosis, arrest of the cell cycle, and upregulation tumor property, correlated with substantially increased oxida-
of the PP2A-GSK-3b-Bax/Mcl-1 axis under hypoglycaemic con- tive stress in cancer cells. The hydrolysis rate of pyridine
ditions, resulting in potent anti-tumor property with few side complex 3-11 was slower than that of its chloride analogue
effects. In all, targeting glucose-mediated energetic metabolism 3-10, resulting in GSH-resistance, cellular Ir accumulation, and
reprogramming is meaningful for organometallic anti-tumor potent cytotoxicity towards cancer cells. Consequently, an acti-
agents. vation time more suitable for transport to biological reaction
sites was obtained. Subsequently, the aqua Ir(III) adduct (Ir–
3.2 Redox homeostasis OH2) of these iridium(III) complexes was shown to participate in
Redox homeostasis is generally regarded as a core component the oxidative reaction of the coenzyme NADH to form NAD+.
that maintains the physiological state. Under normal condi- The production of H2O2 by electron transfer from NADH to O2
tions, cells have fully functional mitochondria153 and scaven- was closely responsible for the activity of 3-11 (Fig. 23(b)). In
ging systems such as glutaredoxins and superoxide dismutases addition, complex 3-11 has a promising therapeutic index
(SOD), which can protect cells from redox stress.154 In tumors, towards cancer cells compared to normal cells.159 The rational
excessive ROS/reactive nitrogen species (RNS) are initiated by design of the organoiridium complex as a novel catalyst to
oncogenic mutations and rapid proliferation, contributing to oxidise NADH is extremely efficient for ROS production.
the miscoding of DNA, inhibition of respiration, etc. In addi- Furthermore, considering that the hypoxic condition
tion, redox homeostasis is closely related to metabolic restricts ROS production in many solid tumors, Sadler and
homeostasis.155 Glucose metabolism is pivotal in redox homeo- co-workers designed a new photo-redox catalysis system based
stasis, as glycolytic intermediates are transported into meta- on cyclo-metalated iridium(III) complex 3-12 (Fig. 24(a)).160 This
bolic networks to generate reducing equivalents such as GSH stable complex with strikingly decreased electron density and
and nicotinamide adenine dinucleotide (NADH), which are high excited-state reduction potential was capable of photo-
determinants of redox potential maintenance. Therefore, per- catalysing NADH to produce NAD" radicals and synergistically
turbing the delicate tumor redox balance may serve as a reducing cytochrome c in hypoxic media. In detail, the highly
promising anti-tumor approach with tumor selectivity. oxidative excited-state intermediate of 3-12 produced by light
Elevating the oxidative stress induced by ROS is an efficient irradiation acquires an electron from NADH to form reductive
method to kill malignant cells.156 Excessive ROS or deficient species of 3-12 and NADH" + radicals, which can deprotonate to
scavenging systems can induce oxidative stress and be toxic to produce NAD" radicals. Oxygen and cytochrome c participate
cells.157 In addition, cancer cells with increased oxidative stress in the photocatalytic cycle to form ROS and NAD+ under
are probably more sensitive to ROS damage.158 Therefore, normoxia and hypoxia, respectively (Fig. 24(e)). Furthermore,
Sadler et al. showed that GSH-tolerant Cp iridium(III) complexes 3-12 interrupted the mitochondrial ETC and induced an imbal-
3-10 and 3-11 (Fig. 23(a)), which featured high potency of anti- anced redox potential. Finally, complex 3-12 induced oxygen-
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Fig. 24 (a) Chemical structure of organometallic complex 3-12 for photocatalytic reactions; (b–d) chemical structures of organometallic complexes
3-13–3-21 for evoking oxidative stress; (e) scheme of the photocatalytic mechanism of 3-12 in normoxic and hypoxic conditions, respectively.
independent immunogenic apoptotic cancer cell death with The activation of redox drugs can be induced by both
moderate side effects. This organometallic photocatalyst can oxidative and reductive stresses. As the Warburg effect is one
elevate cellular oxidative stress regardless of the O2 concen- of the key mechanisms in cancer cells, the conversion of
tration, which opens a new road for O2 deficient tumor treat- pyruvate into lactate by an external synthetic catalyst can
ment. In a more recent study, the same group constructed a set threaten the usage of energy and essential metabolites in
of half-sandwich iodido iridium(III) azopyridine complexes cancer cells.165 Since multiple nucleophilic biomolecules could
3-13–3-18 with a ligand-centred activation mechanism coupled hinder the catalytic activities, an Noyori-type ruthenium
to redox reactions (Fig. 24(b)).161 These unusual reaction path- complex 3-22 was designed to catalyse the reduction of the
ways of iridium(III) complexes involved not only redox activation coenzyme NAD+ to produce NADH using formate rather than
of coordinated azopyridine ligands originating from the GSH acetate as the hydride donor (Fig. 25(a)).166 The [NAD+]/
attack to generate paramagnetic species, but also catalysis of [NADH] ratio decreased after ruthenium complex interven-
hydroxyl radicals and reductive liberation of hydrazopyridine tion in a formate-dependent manner, which directly contrib-
ligands, further resulting in increased GSSG and ROS produc- uted to the elevated antiproliferative activity, consistent
tion, especially for superoxide. As a result, these complexes with the rate of catalytic transfer hydrogenation. Moreover,
exhibited significant cytotoxicity and antiproliferative activity reductive stress could lower the production of ROS but
in cisplatin-resistant A2780R ovarian cancer cells. neither trigger variation in MMP nor apoptosis, resulting in
As osmium(II) arene complexes exhibited nanomolar cyto- cancer cell-specific damage for redox imbalance. This action
toxicity in cancer cells162 with potential for redox modulation, mode was different from that of most anti-cancer agents
Romero-Canelon et al. also synthesised various anti-cancer (Fig. 25(c)). Recently, another stable Noyori-type organome-
Os(II) complexes containing 16 electrons or 18 electrons to tallic osmium complex 3-23 was studied for transfer hydro-
overcome conventional platinum drug resistance.163 Some of genation (Fig. 25(a)).167 This compound was also investigated
these complexes appeared to avoid detoxification by P- for the reduction of pyruvate using sodium formate as a
glycoprotein-induced cellular efflux and exhibited significant hydride source at non-toxic concentrations in both aqueous
toxicity in cisplatin- or oxaliplatin-resistant cells. Electrochemi- systems and tumor models, giving rise to chiral products of
cal studies have shown that the redox mechanism of these lactate with a high conversion and enantiomeric excess,
complexes is related to consecutive one-electron steps along which is important for cell metabolism and survival. Similar
with halide dissociation, and might be responsible for ROS to the Noyori-type ruthenium complex, 3-23 exhibited
production. Furthermore, a new red-fluorescent Os(II) complex enhanced cytotoxicity with an increase in formate concen-
3-19 was synthesised to investigate oxidative stress in a zebra- tration. In the presence of formate, 3-23 also increased the
fish model and subsequently proved that ROS production was population of cells in G1 cell cycle arrest to a higher degree
the major contributor to the anti-cancer mechanism of these without DNA damage. Furthermore, the absence of a hydride
Os(II) arene complexes (Fig. 24(c)). Our group designed two source or replacement of other carboxylates did not increase
cyclo-metalated iridium(III) complexes 3-20 and 3-21 containing toxicity, indicating the occurrence of catalytic reactions in
a 2,2,6,6-tetramethyl-piperidine-1-oxyl free radical (TEMPO) cells. Also, complex 3-23 showed great cancer cell cytotoxicity
moiety as highly efficient photosensitizers (Fig. 24(d)).164 These and selectivity in the presence of formylmethionine, as it can
complexes not only convert NO" to diamagnetic non-radical release formate by the deformylase enzyme, which is over-
species, but also produce singlet oxygen with high quantum expressed in tumor cells (Fig. 25(c)). As tumors with abnor-
yields upon laser irradiation, eventually resulting in excess ROS mal mitochondrial functions are especially sensitive to redox
and elevated mitochondrial oxidative stress in cancer cells. imbalance, these studies provide an attractive strategy for
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Fig. 25 (a) Chemical structures of organometallic complexes 3-22 and 3-23 for evoking reductive stress; (b) chemical structures of organometallic complexes
3-24 and 3-25 for deprotecting catalytic reactions and imaging hydrogen transfer; (c) scheme of organometallics 3-22 and 3-23 for evoking reductive stress.
conferring tumor selectivity to anti-tumor organometallics by by the demand for metal cofactors for all nucleic acids and
catalytic transfer hydrogenation. approximately 30% to 50% of proteins.171 Metals can neither be
In biological processes, organometallics-induced bioorthogo- synthesised nor decomposed under biological conditions;
nal activation is closely related to nucleophilic redox therefore, sustaining metal homeostasis predominantly relies
homeostasis.168 A variety of fascinating applications of bioortho- on kinetic transportation. Metal homeostasis depends on the
gonal catalysis can be imaged, ranging from protecting substrates/ dynamic balance of two pools: a static pool such as metallo-
prodrugs to catalytically labeling or devitalising target bio- proteins and a labile pool where metals are weakly bound to
molecules. Meggers et al. presented organometallic ruthenium(I) some low molecular weight ligands.172 The alteration of metal
complex 3-24 for catalytic in-cell uncaging reactions (Fig. 25(b)).169 homeostasis includes elimination of excess cellular metal,
This complex efficiently transformed bioorthogonal O-allyl carba- redistribution of metals in tissues, and accumulation of metals
mates into respective amines in the presence of strong nucleo- to toxic levels in the nidus. Many chelators and ionophores can
philes. In further applications, the caged fluorophore or drug (e.g. remove or redistribute metals to achieve therapeutic effects,
N-(allyloxycarbonyl)-aminocoumarin or N-(allyloxycarbonyl)doxor- and metal transport proteins have emerged as pharmaceutical
ubicin) was controllably activated with GSH participation. This targets for inhibiting metal uptake and trafficking.
organometallic catalyst takes advantage of cellular redox homeo- As the most abundant essential transition metal for
stasis rather than disturbance and exhibits potential for tracking humans, iron is crucial for physiological processes.173 An
and retarding tumor progression. In a recent paper, Do et al. abnormally high level of iron is closely related to tumorigenesis
investigated the cellular imaging of iridium catalyst-induced in various cancer types by catalysing the generation of muta-
hydrogen transfer inside living cells.170 Complex 3-25 could genic ROS, interrupting DNA replication, upregulating onco-
catalyse aldehydes into alcohols in the presence of a hydride genes, affecting signal transduction, arresting cell cycle
source, as evidenced by the fluorescence of the BODIPY-OH progression, and acting as a necessary nutrient for proliferating
sensor (Fig. 25(b)). This catalyst acquired the proton from endo- tumor cells.174 As Fe2+ is known as a cofactor that mediates
genous NADH and transferred it to BODIPY-CHO in NIH-3T3 DNA, RNA, and histone demethylate reactions,175 our group
mouse embryo fibroblast cells and A549 human epithelial cancer designed a mitochondria-targeted Re(I) complex 3-26 with an
cells. Subsequently, BODIPY-CHO was reduced to the fluorescent iron chelating moiety deferasirox for perturbing iron home-
BODIPY-OH. Theoretically, the enhanced fluorescence indicates ostasis to achieve anti-cancer goals (Fig. 26(a)).176 Due to the
the oxidative level of NADH in mammalian cells upon organoir- high requirement for iron and reprogramming iron metabo-
idium complex treatment. This work not only investigated the lism in TNBC cells,177 this Re complex showed great selective
catalytic properties of the Cp*Ir complex but also provided a cytotoxicity in TNBC cells and induced immunogenic apopto-
strategy for sensing cellular hydrogen transfer. sis. Iron homeostatic investigation revealed that 3-26 hijacked
Taken together, hindering the cellular redox balance plays a cytoplasmic iron and transferred this part of the iron to the
crucial role in the lethality of organometallic agents and mitochondria, resulting in a significant increase in mitochon-
provides an attractive approach for fighting against intractable drial ROS and disordered energy homeostasis in both
diseases such as cancer. OXPHOS and glycolysis. This Re complex also disturbs epige-
netic modifications during the relocation process of cellular
3.3 Metal homeostasis iron. 5-Methylcytosine (5mC) and N6-methyladenosine (m6A)
Metal ions such as iron, copper, zinc, and calcium are essential are the most abundant modifications in DNA and mRNA,
for bioenergetic and biogeochemical processes, as exemplified respectively, and are involved in cancer development.178,179
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Fig. 26 (a) Chemical structure of organometallic complex 3-26 relocating the cellular iron ion to regulate tumor epigenetics; (b) chemical structure and
working mechanism of 3-27 perturbing iron homeostasis.
H3K9 methylation is also closely related to the silencing of the and necroptosis, and exhibited superior anti-tumor activities
cancer suppressor gene.180 Thus, mechanistic studies showed with minimal side effects in vivo.
that 3-26 made mitochondrial metabolism disordered and Intracellular calcium serves as a second messenger and
affected the expression of key epigenetic metabolites such signal transducer in both excitable and non-excitable cells,
as a-ketoglutarate (a-KG), succinate, fumarate, S-adenosyl- and can induce necrosis and apoptosis related to carcino-
methionine (SAM), and S-adenosylhomocysteine (SAH) which genesis.183 Calcium ions access the extracellular space through
are correlated to the activity of 2-oxoglutarate/Fe(II)-dependent calcium-selective channels in the plasma membrane and are
demethylases.181 As a result, complex 3-26 further induced simultaneously released from intracellular calcium stores to
deactivation of relative enzymes and elevation of the methyla- achieve cellular ion balance, which is often associated with the
tion levels of typical 5mC, m6A, H3K4Me3, and H3K9Me3 in a mitochondria and endoplasmic reticulum (ER). One of the
dose-dependent manner. As histone/DNA/RNA methylation can most significant events correlated with calcium signalling is
affect chromatin state and gene transcription, 3-26 subse- the activation of cell death pathways that are regulated by the
quently altered RNA polymerase II-related gene expression, binding of calcium to calcium-sensor proteins.184 Aoki et al.
resulting in cancer cell death. developed a series of iridium(III)–peptide hybrids to achieve
Considering that the oxidative form of Fe3+ accumulates in anti-cancer effects through intracellular calcium homeostasis
lysosomes and is associated with the progression of gastric perturbation.185,186 The typical hybrid 3-28 containing a catio-
cancer, Chao et al. designed a lysosome-located Fe3+ ion- nic peptide KKGG (K: lysine, G: glycine) could bind to the
activated iridium(III) complex 3-27 with a chelated catechol unit calcium calmodulin complex and cause the overload of intra-
(Fig. 26(b)).182 This non-luminescent complex can be oxidised cellular calcium to destroy calcium balance and exhibit high
by two equivalents of cellular labile Fe3+ to form a Schiff base toxicity in cancer cells (Fig. 27(a)). In detail, complex 3-28
which is unstable in lysosomes and simultaneously releases transferred cellular Ca2+ from the ER to the mitochondria,
Fe2+ to perturb iron homeostasis. After acidic stimulation, the evoked ER stress and induced depolarisation of the mitochon-
Schiff base was hydrolysed to form an aminobipyridyl complex dria with decreased MMP. Consequently, this complex trig-
and 2-hydroxybenzoquinone with obvious phosphorescence gered the paraptosic pathway in a Ca2+-dependent manner, as
recovery, which endowed 3-27 with the ability to monitor evidenced by cytoplasmic vacuolisation resulting from
cellular labile iron. Complex 3-27 also exhibited excellent damaged ER and mitochondria (Fig. 27(b)).185 Furthermore,
selectivity for Fe3+ over other biologically relevant metal ions, another iridium(III)#peptide hybrid 3-29 quickly accumulated
such as Na+, K+, Mg2+, Mn2+, Ca2+ and Zn2+, and reliably in Jurkat cells and induced attachment of mitochondria
distinguished Fe3+ from Fe2+ with negligible impact of ROS. and ER via mitochondria-associated membrane interruption
Therapeutically, the released 2-hydroxybenzoquinone is a (Fig. 27(a)). In synergy with CGP37157, a typical inhibitor of
strong ROS generator that reacts with GSH and NADPH to mitochondrial Na+/Ca2+ exchanger, complex 3-29 promoted
produce hydroxyl radicals via the Fe2+-catalysed Fenton reac- membrane fusion between mitochondria and ER by cellular
tion. Thus, complex 3-27 showed selective cytotoxicity in ferric Ca2+ rearrangement, leading to calcium flux from ER to mito-
ion-enriched gastric cancer cells through inducing apoptosis chondria with alteration of membrane permeability (Fig. 27(b)).
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Although current metal homeostasis studies mostly focus on

iron and calcium, investigations of other endogenous essential
metal homeostasis, such as zinc, copper, manganese, and
cobalt homeostasis, are also extremely valuable for revealing
the relationship between metal homeostatic state and patholo-
gical mechanisms. The regulated networks between anti-cancer
organometallics and more endogenous metals are highly
encouraged for supplementation.
3.4 Immune homeostasis

Immune homeostasis plays a major role in the dynamic tumor
progression. CD8+ cytotoxic T lymphocytes (CTL), B cells, and
natural killer (NK) cells are key components of immune
defense, while regulatory T lymphocytes (Tregs) and myeloid-
Fig. 27 (a) Chemical structures of organometallic complexes 3-28 and 3-
derived suppressor cells (MDSCs) can inhibit excessive immune
29 intervening in calcium homeostasis; (b) scheme of calcium arrange-
ment induced by iridium(III)–peptide hybrids 3-28 and 3-29. responses. Typically, the antigen-presenting cells phagocytize
and internalize tumor cell debris, subsequently delivering
tumor antigen to recruit CTLs and triggering Fas/FasL
pathway-mediated apoptosis (‘‘hot’’ tumor).193 However, plenty
The overloaded Ca2+ in mitochondria impacted mitofusins and of tumors present immune evasion to support their growth and
other relevant molecules, and induced the loss of MMP to metastasis (‘‘cold’’ tumors).194 The so-called ‘‘tumor immune
ultimately result in lethal paraptosis.186 These pioneering microenvironment (TIME)’’ involves senescence and exhaus-
works highlight the relationship between calcium homeostasis tion of immune cells, tolerance of antigen-presenting cells,
and cancer cell death, which may enlighten a more rational release of immunosuppressive chemokines and so on.195 For
design of organometallics to specifically perturb calcium example, indoleamine 2,3-dioxygenase (IDO) overexpressed in
homeostasis. tumors perturbs the functions of CTLs and NK cells, but
Zinc is another essential micronutrient that plays vital roles promotes the function of Tregs.196 Additionally, the lack of
in cell development, and excess zinc is also implicated in wild type TP53, a typical cancer suppressor gene, facilitates
cancer progression.187 Many organometallics have been secretion of chemokines to polarise the tumor-associated
reported for intracellular Zn2+ imaging. For example, Lo et al. macrophage from immunoactivating M1-phenotype to immuno-
developed a tricarbonylrhenium(I) complex to exogenously suppressive M2-phenotype (tumor-associated macrophage,
monitor Zn2+ in human cervix epithelioid carcinoma cells TAM).197 Thus, converting the immune ‘‘cold’’ tumors to
imaged by ion-dependent luminescence.188 Ma and co- ‘‘hot’’ tumors can be a main dynamic regulation to promote
workers also investigated a cyclo-metalated iridium complex anti-cancer immunotherapy.
as the zinc-specific luminescent receptor with a change in Cancer is a chronic inflammatory disease. Both innate and
luminescence color from blue to green upon addition of adaptive immune cells contribute to the inflammatory tumor
Zn2+.189 In addition, Lippard et al. demonstrated an iridium- microenvironment, which may either promote or inhibit
based zinc chelator with ratiometric luminescence responses tumorigenesis.195 The inflammatory response in tumors is
and ion-dependent luminescence lifetimes to image cellular ascribed to chronic inflammation, which can lead to the
Zn2+ in biological samples.190 These findings cause extensive infiltration of innate immune cells and secretion of substances
concerns in labile zinc biology, but much is still unknown responsible for angiogenesis and cell proliferation. Since nitric
about the mechanisms of its homeostasis, which deserves oxide (NO) generated by inducible nitric oxide synthase (iNOS)
further Zn2+-mediated therapeutic investigations. plays pivotal roles in angiogenesis, vascular permeability and
Copper homeostasis is important in all forms of organisms. inflammation, Leung et al. prepared a rhodium(III) complex
Copper is required as a catalytic cofactor or structural consti- 3-30 to impair lipopolysaccharide (LPS)-induced NO production
tuent for proteins and plays critical roles in physiological for inflammation relief and antiangiogenesis (Fig. 28(a)).198
processes. Many types of cancer exhibit increased intratumoral Complex 3-30 inhibited nitrite generation induced by LPS, an
copper or redistributive endogenous copper, which could influ- endotoxin that can bind to the CD14/TLR4/MD2 receptor
ence tumorigenesis, angiogenesis and metastasis.191 Lippard complex, to promote the secretion of pro-inflammatory cyto-
et al. developed a multi-chromophoric iridium(III) complex with kines and NO in RAW264.7 macrophages in a dose-dependent
a copper ion receptor for sequestering and quantifying Cu2+ manner. The inhibitory efficiency of 3-30 was even more
inside cells with stable green emission and altered red superior to that of the acknowledged inhibitors iNOS and
emission.192 This work also inspired the development of ion- S-methylisothiourea sulfate. Furthermore, complex 3-30
intervened therapy by disturbing the cellular copper balance repressed NF-kB luciferase activity in luciferase-transfected
through a combination of organometallics with chelated RAW264.7 cells and downregulated the transcriptional activity
moieties. of nuclear factor-kB (NF-kB). As a possible result, complex 3-30
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Fig. 28 (a–c) Chemical structures of organometallic complexes 3-30–3-32 intervening in inflammation; (d) scheme of inflammation disturbance by
organometallics 3-30–3-32.
reduced the levels of tumor necrosis factor a (TNF-a), inter- stimulated anti-tumor immunity. This mixed type of photo-
leukin (IL)-1b, and interferon-g involved in inflammation and sensitizer anchored on the cancer cell membrane and
immunity, subsequently inhibiting the expression of vascular destroyed membrane integrity. Subsequently, 2-60 induced
endothelial growth factor and exhibiting anti-vasculogenic the expression of cleaved capase-1 and gasdermin D, resulting
activity related to cancer cell motility (Fig. 28(d)). Furthermore, in pyroptosis. With cell membrane rupture, damage-associated
Ma et al. also synthesised a benzofuran-conjugated iridium(III) molecular patterns were released to the extracellular space and
complex 3-31 for prostate cancer treatment by inhibition of promoted tumor immunogenicity (Fig. 29(c)). In a 4T1 xeno-
inflammation-associated factors (Fig. 28(b)).199 Complex 3-31 graft mouse model, 2-60 facilitated the maturation of DCs to
obviously suppressed IL-6-induced STAT3-driven luciferase present tumor antigens and then recruited CTLs to ablate both
activity in a benzofuran-dependent manner in human prostate primary and distant tumor with little systemic toxicity. Since
cancer DU145 cells and blocked the translocation of STAT3 ferroptosis is a programmed cell death pathway associated with
from the cytoplasm to the nucleus, resulting in a lower binding iron homeostasis, a ferrocene-modified cyclo-metalated Ir(III)
capacity of STAT3 with nuclear DNA. Meanwhile, complex 3-31 complex 3-33 was prepared by our group for cellular Fenton
also prevented the translocation of NF-kB induced by TNF-a in reaction to achieve ferroptosis-enhanced cancer immunity
DU145 cells, and further affected downstream proteins regu- (Fig. 29(a)).201 Depending on Fe2+/Fe3+ conversion, complex
lated by STAT3 and NF-kB signalling such as c-Myc and Bcl-2, 3-33 can serve as a biological catalyst to initiate cellular Fenton
which are closely related to cancer progression (Fig. 28(d)). reaction by catalyzing hydrogen peroxide to produce highly
Furthermore, MTT and lactate dehydrogenase leakage assays toxic hydroxyl radicals. The best catalytic activity of complex
showed that complex 3-31 exhibited violent cytotoxicity in
DU145 cells accompanied with plasma membrane damage
and lactate dehydrogenase release, resulting in excellent anti-
cancer property in vitro. Eventually, complex 3-31 also signifi-
cantly inhibited RM-1 transplantable tumor growth in a xeno-
graft C57 mouse model. In addition, given the rise of apoptosis-
resistant tumors, Yoldi and co-workers introduced an alkynyl
gold(I) complex 3-32 as an initiator of necroptosis with an
inflammatory reaction (Fig. 28(c)).200 This alkynyl gold(I)
complex could bind to bovine serum albumin with the phe-
nomena of fluorescence quenching, and the binding constant
was found to be 2.3 $ 108 M#1, demonstrating the high affinity
between 3-32 and this protein. Furthermore, complex 3-32 with
appropriate amphipathy accumulated in cancer cell mitochon-
dria and fiercely elevated ROS levels, subsequently stimulating
TNF-mediated necroptosis with clear swelling. Through the
activation of inflammation-related receptor-interacting protein
1 and NF-kB, complex 3-32 displayed therapeutic effects against
cancerous cells. These above-mentioned works take advantage
of the ‘‘double-edged sword’’ character of inflammation to
cancer immunity, and provide new clues for the design of
organometallic immune-modulators.
Accumulating evidence demonstrates that effector T cells
can prevent tumor development by triggering pyroptosis, fer-
Fig. 29 (a and b) Chemical structures of organometallic complexes 3-33
roptosis, apoptosis, and other cell death pathways.197 As men- and 3-34 initiating ferroptosis and apoptosis to evoke anti-tumor immu-
tioned in Section 2.2, our group presented a CA IX-anchored nity, respectively; (c) illustration of T cell rearrangement by organometal-
rhenium(I) photosensitizer 2-60, which could evoke pyroptosis- lics 2-60, 3-33 and 3-34.
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Table 2 Representative examples of bioprocesses intervened by organometallic complexes
Biological processes Key molecules Key pathways Organometallic type Metal Ref.
Metabolism reversion PDK, ND5, ATM, p53, p21 ETC, glycolysis Metal carbonyl, metal arene Re, Os 138 and 139
ATP restraint mtDNA, NADH, cytochrome c, TCA cycle, ETC, chromosomal Cyclo-metalated complex, Ir, Au 142,144,145,147
TrxR, LC3B instability, PI3K signalling metal acetylide and 148
Glucose homeostasis Glucose, AMPK, GSH, mTOR, Autophagic flux, PP2A-GSK-3b- Cyclo-metalated complex, Au, Os 151 and 152
TrxR, HK2, PKM2, LDHA Bax/Mcl-1 axis metal arene
Oxidative balance NADH, cytochrome c, GSH TCA cycle, GSH oxidation, Cyclo-metalated complex, Ir, Os 159–161,163 and
NADH oxidation metal Cp, metal arene 164

+
Reductive balance NAD , pyruvate, formate, TCA cycle, pyruvate metabo- Metal arene Ru, Os 166 and 167
formylmethionine lism, NAD+ reduction
Deprotected catalytic NADH, thiols NADH oxidation Metal Cp, metal arene Ru, Ir 169 and 170
reaction
Iron homeostasis GSH, NADPH, a-KG, SAM, TCA cycle, one carbon meta- Cyclo-metalated complex, Ir, Re 176 and 182
SAH, succinate, fumarate, bolism, histone/DNA/RNA metal carbonyl
TET, FTO, 5mC, m6A, methylation, apoptotic and
H3K4Me3, H3K9Me3 necroptotic pathway
Calcium homeostasis Calmodulin Calcium ion flux, ER stress Cyclo-metalated complex Ir 185 and 186
Inflammatory state iNOS, NF-kB, TNF-a, STAT3, NF-kB signalling, STAT3 Cyclo-metalated complex, Rh, Au, 198–200
IL-6, c-Myc, Bcl-2, VEGF signalling metal acetylide Ir
T cell rearrangement GPX4, NADPH, CRT, HMGB1, Lipid peroxidation, T cell acti- Cyclo-metalated complex, Ir, Ru, 109,201 and 205
CD4, CD8 vation and differentiation metal arene, metal carbonyl Re
3-33 was determined at pH 5.5, which is close to the lysosomal capability with decreased vessels, which was also related to
pH (B4.5–5.5). Furthermore, complex 3-33 induced lipid per- immunosurveillance. Analyses of immune cells suggested that
oxidation and downregulated glutathione peroxidase 4 with besides the elevated infiltration levels of immune cells which
GSH and NADPH oxidation, resulting in the activation of are beneficial for immunosurveillance such as M1 macro-
ferroptosis and ICD. Simultaneously, RNA sequencing analysis phages, matured DCs, and CTLs, the recruitment of Tregs in
also identified genes related to cytokine production and bio- 3-34-treated samples decreased significantly with the reduction
synthesis as well as T cell activation and differentiation, indi- of COX-2, a protein associated with cancer progression
cating potential immune responses. The damage-associated (Fig. 29(c)).
molecular patterns induced by 3-33 such as calreticulin, ATP, In summary, tumor homeostasis perturbation could be a
and high mobility group box-1 protein were observed to be promising strategy for cancer treatment. The representative
released from cancer cells to the extracellular matrix, thereby homeostatic processes and their corresponding key regulators
promoting the maturation of dendritic cells (DC) to present and pathways are briefly summarised in Table 2. Inspired by
tumor-specific antigens in tumor-draining lymph nodes. In this, the rational design of organometallic agents that can
addition, this complex further induced an increase in pro- dynamically intervene in tumor metabolic energy, redox
inflammatory cytokines and a decrease in anti-inflammatory potential, essential metal balance, and immune deployment
cytokines, leading to the transformation of native T cells to is expected to be a promising strategy to achieve good anti-
CD4+ and CD8+ T cells for anti-cancer immune response cancer efficacy and study physiological and pathological issues
enhancement in vivo (Fig. 29(c)). in-depth. In the future, the relationship between tumors and
In addition to increasing the tumor infiltration of CTLs, other homeostatic modes, such as biomolecular condensation
inhibiting Tregs is an effective strategy to elicit anti-cancer and intracellular anions, remains to be further investigated.
immunosurveillance. Tregs play key roles in tumor develop-
ment by suppressing the proliferation of effector T cells or
directly killing them through granzyme and perforin.202,203 4. Anti-tumor organometallics
Simultaneously, cytokines such as transforming growth fac- triggering cell death pathways
tor-b and IL-10 secreted by Tregs also contribute to the devita-
lisation of tumor-associated CTLs.204 Thus, Amici et al. When tumor homeostasis is perturbed, multiple outcomes can
designed a ruthenium(II) complex 3-34 with p-cymene featuring be triggered, among which cell death plays a dominant role.
excellent immunotherapeutic activity (Fig. 29(b)).205 This com- Cell death is a crucial process during tumor growth, progres-
pound exhibited better lethality than NAMI-A or cisplatin in sion, and homeostasis, and defects in cell death pathways are
mouse A17 or human MB-MDA-231 TNBC cells and potent pro- often regarded as hallmarks of cancer. Since the cell death
apoptotic ability and antiangiogenic effects in a dose- mode is able to significantly affect the efficacy of anti-cancer
dependent manner in vivo. Complex 3-34 significantly inhibited agents, targeting a specific cell death pathway is emerging as a
A17 transplantable growth with few side effects, as evidenced useful therapeutic strategy to eradicate cancer cells and miti-
by stable mouse weights and minimal nephrotoxicity/hepato- gate drug resistance.206 The understanding of cell death path-
toxicity, which was much better than cisplatin treatment. ways is constantly evolving as a new cell death mode termed
Furthermore, complex 3-34 also demonstrated antiangiogenic ‘‘cuproptosis’’ induced by copper was freshly proposed by
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Fig. 30 Main cell death pathways have been identified to date that can be induced by organometallics.
Golub and Tsvetkov et al.207 At present, to the best of our downstream executioner caspases such as caspase-3, -6, and
knowledge, nine major cell death pathways have been revealed -7, eventually inducing extrinsic apoptosis. Moreover, caspase-8
to be efficiently triggered by anti-tumor organometallic com- is also able to cleave the Bcl-2-homology 3 (BH3)-only protein
plexes (Fig. 30). In this section, the recent progress in organo- Bid, subsequently promoting the activation of pro-apoptotic
metallics that can induce diverse cell death pathways including proteins Bax and Bak. These proteins are also associated with
classical apoptosis, paraptosis, autophagy, oncosis, necropto- the intrinsic pathways. Usually, the intrinsic pathway is trig-
sis, necrosis, and burgeoning ferroptosis, pyroptosis, and gered by stimuli such as DNA damage. Because of the resulting
immunogenic cell death (ICD) is reviewed, and the character- cellular stress, BH3-only proteins are activated and suppress
istic morphological and biochemical criteria of each cell death the anti-apoptotic Bcl-2 family members, thus alleviating
mode are summarised. their inhibitory effect on Bax and Bak. Consequently, the
oligomerization of Bax and Bak generates a channel for the
4.1 Apoptosis and paraptosis transportation of cytochrome c from the mitochondria to the
The term ‘‘apoptosis’’ was firstly introduced by Kerr and co- cytosol. Once released, cytochrome c interacts with apoptotic
workers to describe a form of programmed cell death featuring protease-activating factor 1 (Apaf-1) and ATP to form the
specific morphological changes.208 Since then, apoptosis serves apoptosome, a platform for recruiting and activating pro-
as the principal mechanism of cell death caused by chemother- caspase-9. Like caspase-8, activated caspase-9 is capable of
apeutics. Morphologically, during apoptosis, cell shrinkage, cleaving and activating the downstream caspase-3, -6, and -7
membrane blebbing, chromatin condensation, and apoptotic to trigger the intrinsic apoptotic pathway. In addition, apart
body formation can be observed, followed by cell breakdown from cytochrome c, other pro-apoptotic proteins released from
into apoptotic bodies and being swallowed by surrounding cells the mitochondria, such as SMAC/DIABLO, can bind with inhi-
and phagocytes.209 There are two main signalling pathways that bitors of apoptosis proteins (IAPs) to further promote the
initiate apoptosis: the extrinsic (receptor-activated) pathway activation of caspase-3, -7 and -9.209
and the intrinsic (mitochondria-mediated) pathway. Tumor As the principal cell death mode, examples of organometal-
necrosis factor superfamily (TNFSF) and B-cell lymphoma 2 lics as apoptosis-inducers are quite abundant. For instance, a
(Bcl-2) family members are key biomolecules for extrinsic and rhenium(I) carbonyl complex 4-1 (Fig. 31(a)) that can trigger
intrinsic pathways, respectively, and the caspase family is both extrinsic and intrinsic apoptotic pathways was developed
essential for both apoptotic pathways.210 The extrinsic pathway by the Metzler-Nolte group.211 In a typical annexin V and
starts from the interaction between TNFSF death ligand and propidium iodide (PI) double staining experiment, complex
receptor, resulting in the formation of the death-inducing 4-1 showed a rapid and high apoptosis induction ability in two
signal complex (DISC) that can recruit and activate caspase-8 tumor cell lines, Nalm-6 (leukaemia) and BJAB (lymphoma),
and/or -10. Subsequently, caspase-8 cleaves and activates while a remarkable decrease in apoptotic cells was observed in
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Fig. 31 (a) Chemical structures of representative organometallics as apoptosis inducers; (b) the brief illustration of extrinsic and intrinsic apoptosis
signalling pathways.
4-1-treated non-malignant leukocytes under the same condi- interactions and p% % %p stacking. Therefore, these organometal-
tions. Gene expression analysis revealed that TNFRSF1A, lics 4-2 and 4-3 underwent efficient cell uptake via endocytosis,
TNFRSF1B, and APAF1 were dramatically upregulated in BJAB whereas coordination complex 4-4 was taken up by the cell by
cells after complex 4-1 treatment. TNFRSF1A and TNFRSF1B energy-independent passive diffusion. As a result, complexes
encoding for ligand-bound receptors are related to the FAS 4-2 and 4-3 feature superior cellular uptake and in vitro and
receptor pathway, whereas the upregulation of APAF1 strongly in vivo PDT properties compared to 4-4.
indicated the activation of caspase-3 in a cytochrome c- Our group prepared a series of Ir(III) complexes that can
dependent manner. These results indicate that both the extrin- induce extensive cell apoptosis through photo-induced lysoso-
sic and intrinsic apoptotic pathways were induced by this single mal damage.213 Among these, complex 4-5 (Fig. 31(a)) features
molecule. Moreover, the addition of both TNF-a antibody and the highest phototoxicity index (PI) of 4 830 in A549 cells, and
caspase-8 inhibitor partially inhibited the induced apoptosis, this complex is applied to monitor lysosomal integrity during
verifying a TNF-initiated and caspase-8 activated extrinsic the PDT process due to its specific lysosome accumulation
apoptosis pathway. Meanwhile, when incubated with the mod- and photophysical properties. Furthermore, we developed a set
ified BJAB cell line carrying a vector with a downregulated of mitochondria-targeted Ir(III)-bisNHC complexes 4-6–4-8
caspase-3 gene, complex 4-1 underwent an up to 40% lower (Fig. 31(a)) as theranostic and PDT agents.214 After photoirra-
apoptosis induction, highlighting the involvement of caspase-3. diation, these complexes can trigger mitochondrial damage
With the fact that the mitochondrial membrane potential and apoptosis to achieve a cytotoxicity enhancement of up
(MMP) was decreased by complex 4-1 in a dose-dependent to three orders of magnitude. Meanwhile, the morphological
manner, the mitochondria-mediated intrinsic apoptotic path- alteration of mitochondria in HeLa cells caused by complex 4-8
way was also confirmed. Importantly, the apoptosis-inducing was real-time tracked by CLSM. Chao and Gasser et al. recently
ability of complex 4-1 was not affected by the expression of anti- constructed a cyclo-metalated Ir(III) photosensitizer 4-9
apoptotic protein Bcl-2, indicating its potential to overcome (Fig. 31(a)) as a strong apoptosis inducer after photo-
drug resistance. Furthermore, complex 4-1 is proved to effi- excitation.215 Upon two-photon irradiation in the NIR, this
ciently inhibit the proliferation of drug-resistant BJAB and complex was capable of releasing an active Ir(III) complex and
Nalm-6 tumor cell lines at low micromolar concentrations. In generating singlet oxygen from the covalently bound oxygen
summary, complex 4-1 can parallelly induce not only extrinsic molecule as well as the alkoxy radical under hypoxia. Through
apoptosis through the activation of TNF and caspase-8, but also such synergistic PDT and photoactivated chemotherapy (PACT),
intrinsic apoptosis via a caspase-3-mediated mitochondrial this complex showed efficient phototoxicity in hypoxic tumor
pathway, thereby exhibiting great antiproliferative activities cells at low nanomolar concentrations. Mechanistic studies
on a panel of drug-resistant tumor cell lines.211 An overview have revealed that this mitochondria-localised complex induces
of the general mechanism of extrinsic and intrinsic apoptosis is apoptosis by causing mitochondrial dysfunction.
briefly illustrated in Fig. 31(b). The concept of ‘‘paraptosis’’ as a combination of para
Bonnet and Sun et al. reported a set of palladium(II) com- (next to or related to) and apoptosis was firstly dubbed by
plexes 4-2-4-4 (Fig. 31(a)) that can strongly induce tumor cell Bredesen et al. in 2000 to describe a non-apoptotic pro-
apoptosis after blue light irradiation, especially for complex grammed cell death characterised by massive cytoplasmic
4-2.212 Interestingly, unlike the coordination complex 4-4, the vacuolisation, mitochondrial swelling and ER stress.216 Our
cyclo-metalated complexes 4-2 and 4-3 could undergo an group recently reported a cyclo-metalated iridium complex 4-10
unprecedented protein-controlled self-assembly of nanoaggre- that can trigger paraptosis via the mitochondria-mediated
gates in aqueous solution through Pd% % %Pd metallophilic pathway (Fig. 32(a)).217 Morphologically, 4-10-treated A549 cells
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the lysosome through fusing with the lysosome; (3) as a result,

the so-called ‘‘autolysosome’’ is formed; (4) cytoplasmic mate-
rials are eventually degraded by the lysosome.221 Autophagy
plays a vital role in tumor cells for cell adaptation and survival
during stresses like starvation, while excessive autophagy can
also lead to tumor cell death. Microtubule-associated protein
light chain 3 (LC3) is regarded as a marker of autophagy, and
phosphatidylinositol 3-kinase (PI3k), mammalian target of

rapamycin (mTOR), and AMP-activated kinase (AMPK) are also
important factors in the autophagic signalling pathway.
Over the past few years, our group developed a series of
organometallic iridium(III)75,222 and rhenium(I)223,224 com-
Fig. 32 (a) Chemical structures of the representative organometallic plexes as autophagy inducers. For example, a theranostic
paraptosis inducers; (b) the general action mechanism of complex 4-11. iridium(III) complex 4-12 (Fig. 33(a)) with a long emission
wavelength (645 nm), a pKa value (5.19) close to lysosomal
pH, and very high Pearson’s colocalisation coefficient with
exhibited mitochondrial swelling and damage, and subse-
lysosomes (0.91) was selected for simultaneous autophagy
quently the appearance of excessive vacuoles in the cytoplasm
induction and autophagic lysosome monitoring.222 The autop-
with intact plasma membrane and nuclei. Biochemically,
hagy induction ability of this complex in A549 cells was first
complex 4-10 failed to activate caspase-3/-7 and PARP but
validated by TEM and western blotting analyses, in which
impaired the ubiquitin-proteasome system (UPS) and activated
substantial vacuoles containing degraded materials and the
mitogen-activated protein kinases (MAPKs) including ERK and
autophagy-characterised event of LC3-I to LC3-II conversion
JNK. These morphological and biochemical features are closely
were both detected. Then, real-time tracking for lysosomal
associated with paraptosis. Further studies revealed that
morphology alterations during the autophagic process was
complex 4-10 can selectively accumulate in mitochondria and
conducted using CLSM under both one- and two-photon irra-
intervene in mitochondrial physiological functions in a strong
diation. Incubation of complex 4-12 with eGFP-LC3-transfected
and rapid manner. The consequent loss of MMP, ATP deple-
A549 cells resulted in the gradual merging of lysosomes and
tion, mitochondrial respiration dysfunction, and ROS genera-
eGFP-LC3, indicative of lysosomal-autophagosomal fusion.222
tion eventually triggered paraptosis. Moreover, in vitro and
Later on, by utilising an ER-targeted rhenium(I) tricarbonyl
in vivo studies consistently demonstrated that complex 4-10
complex 4-13 (Fig. 33(a)), we further achieved real-time tracking
features strong anti-tumor activity in several tumor cell lines and
of ER turnover during the process of ER degradation by
A549-xenografted mouse models.217 Another mitochondria-
autophagy (ER-phagy) via lifetime imaging. Owing to the
targeted cyclo-metalated iridium(III) complex 4-11 (Fig. 32(a)) pre-
viscosity-responsive emission properties of complex 4-13, we
pared by Patra and Kim et al. also induced paraptosis in MCF-7
observed that the viscosity of ER underwent an initial increase
cells in a similar manner.218 As briefly illustrated in Fig. 32(b),
and a subsequent decrease during ER-to-lysosome-associated
complex 4-11 penetrated the cell membrane and localised in
degradation (ERLAD), indicating that ERLAD plays a role in
mitochondria to induce substantial ROS production. Then,
mitigating ER stress caused by unfolded proteins.224
MAPKs (JNK and ERK) were activated to cause proteasomal
Recently, a ruthenium(II) arene complex that can efficiently
damage and ER stress (CHOP overexpression), leading to ER
trigger autophagy was developed using a bioorthogonally cata-
and mitochondrial swelling and consequent paraptosis. Such
lytic lethality (BCL) strategy introduced by Guo, Liu, and Zhao
mitochondrial enlargement also resulted in further elevation of
et al. Taking advantage of the higher copper content in some
intracellular ROS to enhance this paraptosic pathway.218 In addi-
tion to these cyclo-metalated iridium(III) complexes, other orga-
nometallics such as titanocene219 and rhenium carbonyl95,220
complexes have also previously been reported to induce
paraptosis.
4.2 Autophagy and oncosis

Autophagy is a critical process for cellular homeostasis invol-
ving the degradation of cellular components such as macro-
proteins or even whole organelles by the lysosomal pathway.210
The autophagic process mainly includes four steps: (1) cyto-
plasmic portions are captured by a cup-shaped structure called
phagophore which subsequently extends and closes to form the Fig. 33 (a) Chemical structures of representative organometallic autop-
double-membrane vesicle known as autophagosome; (2) the hagy inducers; (b) the brief schematic illustration of the autophagic
autophagosome delivers its engulfing cytoplasmic contents to process.
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tumor cells than in normal tissues, a copper-catalysed azide The Chao group synthesised a series of mitochondria-
and alkyne cycloaddition (CuAAC) reaction between a targeted cyclo-metalated iridium(III) complexes 4-15–4-18
ruthenium(II) arene azido compound and the same molar (Fig. 34(a)) that can specifically induce oncosis in A549R
amount of alkyne spontaneously proceeds inside tumor cells cells.227 The most prominent morphological changes of
via endogenous copper-mediated catalysis. Remarkably, com- A549R cells treated with these complexes include cytoplasmic
pared with the non-toxic reactants (IC50 4 100 mM for the vacuolisation accompanied by cell rounding and swelling.
Ru(II)-azido compound and IC50 = 46.2–60.7 mM for the alkyne), In addition, as shown in Fig. 34(b), other phenomena
the in situ synthesised triazolato complex 4-14 (Fig. 33(a)) associated with oncosis included ROS overproduction, MMP
exhibited a significant enhancement in cytotoxicity (IC50 = loss, ATP depletion, increased Bcl-2 : Bax ratio, cytoskeleton and
5.6–12.1 mM) towards A549, A2780, and MCF-7 cell lines with plasma membrane collapse, and leakage of lactate dehydro-
higher copper concentrations (41.3–67.9 ppb/107 cells). The genase (LDH), confirming that these complexes induce the
in situ generation of complex 4-14 in A549 cells was confirmed oncosis pathway. Importantly, two characteristic oncosis pro-
by ESI-MS. Meanwhile, such a 1 : 1 mixture of two reactants in teins, calpain 1 and porimin, were activated by these com-
normal cell lines LO2 and HLF with lower copper concentra- plexes, further validating their oncosis induction property. As a
tions (21.6–24.2 ppb/107 cells) did not show this cytotoxicity result, these complexes consistently exhibited strong cytotoxi-
enhancement (IC50 = 53.9 and 67.3 mM, respectively), suggest- city towards more than ten tumor cell lines including cisplatin-
ing that the copper ion concentrations in these cells are too low resistant ones, and only moderate activity on two normal cell
to catalyse this reaction to produce the active complex 4-14. lines.227
Furthermore, complex 4-14 was determined to accumulate in Recently, Herrero and Ruiz et al. designed another
the mitochondria and induce the formation of autophago- mitochondria-targeted iridium(III)-based oncosis inducer 4-
somes and autophagic vacuoles. The increase in the ratio of 19 (Fig. 34(a)) with strong cytotoxicity towards various tumor
LC3-II to LC3-I expression further proved that this complex cell lines.228 This complex caused cell death through an
triggered cell death through the autophagic pathway.225 A brief apoptosis-independent pathway and a cascade of events,
illustration of the autophagic process is shown in Fig. 33(b). including ROS generation, ATP depletion, mitochondrial
Oncosis is a form of accidental cell death that is morpholo- damage, and cell swelling, indicative of the cell oncosis
gically characterised by cell and organelle swelling, mitochon- induced by complex 4-19. Interestingly, due to the intriguing
drial condensation, nuclear chromatin clumping, cytoplasmic photophysical property of complex 4-19, it was detected in vivo
vacuolisation, plasma membrane blebbing and permeability and showed significant oncosis-dependent anti-tumor efficacy
increase, and cytoskeletal collapse.226 This cell death mode is in the Caenorhabditis elegans tumoral model. Moreover, two
normally induced by energy depletion and ionic pumps of the ruthenium(II)- and osmium(II)-arene complexes 4-20 and 4-21
cell membrane impairment, and finally leads to the leakage of (Fig. 34(a)) developed by the Brabec group were also found to
cellular contents such as inflammatory cytokines that can damage result in MDA-MB-231 cell death via oncosis, validated by both
the surrounding cells by inflammation or immune system stimu- oncosis-distinctive morphological alterations and porimin up-
lation. Oncosis is strongly associated with factors such as pre- regulation.229 Due to their coordinated dichloroacetate ligand,
oncosis receptor-induced membrane injury (porimin), uncoupling complexes 4-20 and 4-21 reversed the Warburg effect and
protein 2 (UCP-2), caspase 1, the transcription factor NF-kB, Bax, exhibited great anti-tumor activities against various tumor
Bcl, and the Ca2+-related protein calpain.226 cell lines.
Fig. 34 (a) Chemical structures of representative organometallic complexes as oncosis inducers; (b) the general action mechanism of complexes 4-15–
4-18.
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4.3 Necrosis and necroptosis of cells and rapid plasma membrane rupture were observed
In contrast to apoptosis, necrosis refers to an accidental and after treatment with 4-23, indicating that this complex triggered
uncontrolled form of cell death induced by fierce external cell death via necrosis. Flow cytometry analysis further demon-
stimuli, leading to cytoplasmic and organelle swelling, loss of strated that complex 4-23 could neither induce cell cycle arrest
cell membrane integrity, and release of cellular contents into nor cause externalisation of phosphatidylserine to the outer
the surrounding extracellular space.230 Recently, a dinuclear membrane, validating its necrosis pathway rather than
Ir(III)–Pt(II) complex 4-22 was developed as a necrosis inducer by apoptosis.238
the Chao group (Fig. 35(a)).231 This complex featured strong Necroptosis is a particular form of programmed necrosis.
cytotoxicity against a panel of tumor cell lines including the This pro-inflammatory cell death mode is caspase-independent
cisplatin-resistant A549R. Interestingly, different from the but highly dependent on biomolecules including receptor-
observation with most complexes, annexin V/PI double staining interacting protein kinase 1 (RIPK-1) and 3 (RIPK-3), the mixed
assay revealed that most of 4-22-treated A549R cells were linkage kinase domain-like protein (MLKL) and Z-DNA binding
located in the Q1 area, suggesting necrosis rather than apop- protein 1 (ZBP1).230 The Chao group recently reported a
tosis. Furthermore, complex 4-22 is unable to affect caspase-3/7 ruthenium(II) organometallic complex 4-24 (Fig. 35(a)) that
activity, verifying that this complex cannot induce apoptosis. can trigger necroptosis through dual inhibition of both topoi-
The cytotoxicity of complex 4-22 was proved to be not influ- somerase (topo) I and II.239 As depicted in Fig. 35(b), complex
enced by the pan-caspase inhibitor Z-VAD-FMK, while the 4-24 mainly accumulated in the nucleus and repressed the
necrosis inhibitor Nec-1 weakened its activity by approximately activity of topo I and II, which further caused induced DNA
20%. In addition, the upregulation of receptor-interacting damage and PARP-1 activation. Consequently, the downstream
proteins 3 (RIP3) and leakage of LDH were induced by complex executioner RIPK-1, RIPK-3, and MLKL were activated to finally
4-22. These results indicated that this complex triggered cell lead to necroptosis. In addition, other features of necroptosis
death through necrotic pathways. Mechanistic studies illu- such as ROS elevation, plasma membrane permeabilisation,
strated that complex 4-22 mostly accumulated in mitochondria and cytosolic ATP depletion were also observed, indicating that
and caused mtDNA dysfunction, consequently interfering with complex 4-24 serves as an effective necroptotic inducer.
mitochondrial function, decreasing MMP, and depleting ATP, Complex 4-24 exhibited strong anti-tumor activity in a variety
eventually resulting in cell necrosis.231 of tumor cell lines. In vivo studies demonstrated that complex
Combinatorial synthesis is an approach for the rapid gen- 4-24 could greatly inhibit tumor development in the A549R
eration of a library of complexes with diverse molecular xenografted mouse model with negligible side effects.239
entities.232 In recent years, this approach has also been utilised 4.4 Ferroptosis and pyroptosis
for high-throughput anti-cancer ruthenium and platinum
complex synthesis and cytotoxicity screening by Ang, Lippard, In 2012, the concept of ‘‘ferroptosis’’ was firstly introduced by
Meggers, Reedijk, and Ziegler et al.233–237 Similarly, the Wilson the Stockwell group to identify a form of programmed cell
group applied a one-pot reaction containing three components, death driven by iron-dependent lipid peroxidation.240
namely, an aniline, a pyridine ligand tethered to an aldehyde, Typical morphological alterations associated with ferroptosis
and rhenium(I) pentacarbonyl chloride, for the rapid synthesis mainly include cell swelling, plasma membrane collapse, intact
of a series of rhenium(I) tricarbonyl complexes with different nuclei, mitochondrial shrinkage, mitochondrial cristae
structural motifs.238 Through such a combinatorial synthesis reduction or disappearance, and outer mitochondrial
methodology, complex 4-23 (Fig. 35(a)) was screened out from membrane rupture.241 In terms of biochemical features, the
80 complexes owing to its potential to combat cisplatin- initiation of ferroptosis often requires the accumulation of
resistant tumor cells. Morphological changes such as rounding cellular lipid ROS, peroxides as well as ferrous iron (Fe2+).
Therefore, glutathione peroxidase 4 (GPX4), an enzyme respon-
sible for lipid ROS elimination, serves as a key regulator of
ferroptotic cancer cell death.242 Meanwhile, the intracellular
iron homeostasis and iron-regulated proteins are also impor-
tant for the ferroptotic process.
Guo and Zhao et al. reported a mitochondria-targeted
iridium(III) complex 4-25 (Fig. 36(a)) that exhibited excellent
anti-tumor activity via the ferroptotic cancer cell death
pathway.243 Proteomic analysis of 4-25-treated A2780 cancer
cells revealed that heme oxygenase 1 (HMOX1), an enzyme
involved in the conversion of heme into ferrous iron, biliverdin,
and carbon monoxide, was responsible for this ferroptotic
process. Further observations of cellular ROS elevation, lipid
Fig. 35 (a) Chemical structures of representative organometallic com-
peroxide (LPO) generation, GSH depletion, and iron release
plexes as necrosis or necroptosis inducers; (b) the general action mecha- validated the ferroptosis induction ability of complex 4-25. In
nism of complex 4-24. addition, mRNA transcription qualification, overexpression of
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Fig. 36 (a) Chemical structures of the representative organometallic ferroptosis inducers (complex 3-33 is not shown); (b) the action mechanism of
complex 4-26 as a ferroptosis and apoptosis inducer.
HMOX1 and RNAi-mediated knockdown experiments consis- cytotoxicity, which refers to cytotoxicity without irradiation.
tently demonstrated that complex 4-25 can efficiently activate Upon ultrasound irradiation, complex 4-27 can produce singlet
HMOX1 to facilitate cellular ROS production, lipid peroxida- oxygen, intervene in glutathione metabolism, and downregu-
tion, and iron accumulation, eventually inducing ferroptosis.243 late intracellular GSH and GPX4, further resulting in LPO
Later on, the He, Guo, and Chen group further developed accumulation and eventually inducing ferroptosis. In addition,
another cyclo-metalated iridium(III) complex 4-26 (Fig. 36(a)) complex 4-27 showed better in vivo anti-tumor efficacy by such a
that can induce ferroptosis in tumor cells under hypoxia sonodynamic therapy compared to PDT in a 4T1 tumor bearing
through photoirradiation.244 This complex is mitochondria- mouse model.
targeted and featured an O2-independent type I PDT property, Pyroptosis is an inflammatory form of programmed necrotic
which readily produced " O2# and " OH upon 450 nm light cell death mediated by gasdermin.247 As a substrate of caspase-
excitation. Subsequently, complex 4-26 caused mitochondrial 1 and caspase-11/4/5, gasdermin D (GSDMD) has been identi-
shrinkage, LPO accumulation, GPX4 downregulation, and fied as a pyroptosis executioner. GSDMD can be cleaved by
ferrostatin-1 (a ferroptosis inhibitor)-inhibited ferroptotic cell these inflammatory caspases and release its N-terminal domain
death. Apart from ferroptosis, complex 4-26 was also able to (GSDMD-N), which subsequently binds to membrane phospho-
trigger apoptosis after irradiation, as evidenced by activation of lipids and forms pores on cell membranes.248 Pyroptosis is
p53 and Bax, caspase-9 cleavage, downregulated expression accompanied by cell swelling, large bubbles blowing from the
of Bcl-xl, and loss of MMP (Fig. 36(b)). Therefore, due to plasma membrane, plasma membrane lysis, and chromatin
this synergistic effect of ferroptosis and apoptosis, complex fragmentation. Moreover, inflammatory cytokines such as IL-1b
4-26 exhibited great PDT inhibitory effects on a panel of tumor and IL-18 are released into the extracellular milieu, which can
cell lines and 3D multicellular spheroids under hypoxic alleviate the immunosuppressive tumor microenvironment and
conditions.244 enhance anti-cancer immunity.
The ferrocene-functionalized iridium(III) complex 3-33 devel- To the best of our knowledge, the CA IX-targeted rhenium(I)
oped by our group can efficiently induce ferroptosis as well as tricarbonyl complex 2-60 is the first reported organometallic
catalyse intracellular Fenton-like reactions (discussed in Sec- pyroptosis inducer.109 As illustrated in Fig. 37, due to the
tion 3.4).245 Due to such a Fenton reaction, " OH was produced benzene sulfonamide group, complex 2-60 anchored on the
in lysosomes and subsequently triggered oxidative stress via cell membrane through binding with the transmembrane
GSH depletion and LPO accumulation, eventually inducing protein CA IX. Upon light irradiation, substantial ROS and
ferroptosis. The ferroptotic pathway was proven by both mor- LPO were generated in situ, resulting in a gradual loss
phological alterations, such as mitochondrial shrinkage with of membrane integrity. This process can be real-time moni-
increased bilayer membrane density and intact nucleus, and tored by this membrane-anchored photoluminescent complex
biochemical features including GPX4 inactivation and tran- through CLSM. Consequently, inhibition of CA IX inactivated
scriptional upregulation of ferroptosis-related genes HMOX1 HIF-1a to overcome hypoxia, and the produced LPO down-
and glutathione specific g-glutamylcyclotransferase 1 (CHAC1). regulated the expression of GPX4 and activated cleaved
Quite recently, a cyclometalated platinum-cyanine complex caspase-1. Subsequently, caspase-1 cleaved GSDMD and
4-27 has been synthesised (Fig. 36(a)) and revealed to be a released GSDMD-N to eventually trigger pyroptosis. In the
ferroptosis inducer after ultrasound irradiation by the Zhang meantime, along with membrane rupture, damage-associated
group.246 This sonodynamic anti-tumor agent features low dark molecular patterns (DAMPs) related to ICD and some
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induced and generally regarded as biochemical hallmarks of

ICD: (1) the Ca2+ binding chaperon protein calreticulin (CRT) is
translocated from the ER-lumen to the cell surface caused by
ER stress serving as an ‘‘eat me’’ signal for the host immune
system; (2) ATP is released from damaged cells by an autopha-
gic process acting as a chemoattractant and a ‘‘find me’’ signal
for macrophages and DCs; (3) during late apoptosis, the
nuclear high-mobility group box 1 (HMGB1) protein is exported

from dying cells and functions as a ‘‘danger’’ signal by extra-
cellularly binding to some receptors such as the toll-like
receptors (TLRs) on innate immune cells.253
In recent years, an accumulating number of metal com-
plexes have been identified as potential ICD inducers, and
Fig. 37 The general action mechanism of 2-60 to trigger pyroptosis.
some recent reviews are available in this emerging
field.254–256 Interestingly, oxaliplatin, rather than cisplatin,
inflammatory cytokines including IL-1b and IL-18 were was found to bear ICD induction ability.257 The pioneering
released, facilitating a series of anti-tumor immune responses organometallic ICD inducer was a platinum(II)–NHC complex
such as DC maturation and T cell activation. Due to these 4-28 (Fig. 38(a)) screened out from a library of platinum
multiple effects, complex 2-60 demonstrated excellent PDT complexes by the Ang group in 2015.258 This ER-localised and
activity towards MDA-MB-231 cells under hypoxic conditions highly cytotoxic complex259 induced cellular ROS elevation and
(lightIC50 = 20 nM vs. darkIC50 4 100 mM) in vitro and great tumor ER stress, and consequently caused CRT translocation, ATP
growth inhibitory efficacy on both primary and distant tumors release, and HMGB1 exposure, which are fully in accordance
in vivo without systemic toxicity in treated mice. with the hallmarks of ICD. In this study, ROS-mediated ER
To date, reports on metal-based complexes as pyroptosis stress was shown to initiate ICD, indicative of the essentiality of
inducers are quite limited.109,249 Indeed, pyroptosis is often ROS and ER stress for ICD induction. Later, the same group
associated with immune responses such as ICD and the cyclic reported another complex 4-29 (Fig. 38(a)) by conducting minor
GMP-AMP synthase (cGAS)-stimulator of interferon genes structural alterations to complex 4-28.260 Compared with 4-28,
(STING) pathway. As a DNA sensor, cGAS can be activated by 4-29 exhibited superior immunogenic properties due to its
both endogenous and exogenous DNA to produce the second ability to induce stronger phagocytosis and immunogenic
messenger cyclic GMP-AMP (cGAMP), which can be detected by DAMP release. Especially, complex 4-29 stimulated the protein
the cyclic-dinucleotide sensor STING, and subsequently evoke a kinase RNA-like endoplasmic reticulum kinase (PERK)-specific
strong type I interferon response that leads to innate anti- arm of the unfolded protein response (UPR) via selective
cancer immunity.250 For example, our group developed a series phosphorylation of eIF2a, which subsequently resulted in
of platinum coordination complexes that can simultaneously CRT translocation for ICD signalling. In addition, this complex
induce pyroptosis and the cGAS-STING pathway after further activated HSP90 as an additional ‘‘eat me’’ signal,
photoactivation.251 In general, considering the tight connection whereas complex 4-28 could only induce CRT translocation.
between pyroptosis and immunity, more organometallics are Based on the ICD induction capacity of these platinum(II)-NHC
expected to be rationally developed for pyroptosis induction complexes, the authors implied that the efficiency of platinum
and cancer treatment. accumulation and ROS production in ER organelles plays
pivotal roles in their ICD potency.260
Arambula, Sessler and Cui et al. designed a redox-active
4.5 Immunogenic cell death (ICD) gold(I) complex 4-30 (Fig. 38(a)) bearing two NHC ligands as an
The important role of the immune system in cancer chemother- efficient ICD inducer both in vitro and in vivo.261 This complex
apy has been gradually recognised in recent years, which was exhibited much higher cytotoxicity (at the nanomolar level)
further promoted by the 2018 Noble Prize in Physiology and towards A549, HCT116 and CT26 tumor cell lines than aurano-
Medicine to James P. Allison and Tasuku Honjo for their fin, and induced a substantial amount of ROS production
discovery of ‘‘cancer therapy by inhibition of negative immune inside cells. Complex 4-30 was further turned out to induce
regulation’’. As an immunostimulatory cell death pathway, the cell membrane CRT translocation, ATP secretion, and
immunogenic cell death (ICD) has recently been defined by HMGB1 release, indicative of its ICD induction ability. Impor-
the Nomenclature Committee on Cell Death (NCCD) as ‘‘a form tantly, the ICD efficacy of this complex was also examined
of regulated cell death that is sufficient to activate an adaptive in vivo using immunocompetent mice in a bilateral CT26 tumor
immune response in immunocompetent syngeneic hosts’’.252 injection model. The results showed that complex 4-30 could
This stress-induced ICD mode involves inflammatory response inhibit the growth of distant tumors, verifying its in vivo ICD
stimulation that could facilitate the activation of CTL-triggered efficacy.261 Quite recently, another redox active gold(I)-NHC
adaptive immunity and establish a long-lasting immunological complex 4-31 was screened out from 40 compounds as an
memory. During the ICD process, three major DAMPs are ICD inducer with great anti-tumor activity (Fig. 38(a)).262 Apart
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Fig. 38 (a) Chemical structures of representative organometallic ICD inducers (complexes 2-60 and 3-33 are not shown); (b) brief illustration of the ICD
mechanism.
from the three typical ICD hallmarks, complex 4-31 can also DAMPs in melanoma cells. Mechanistic studies indicated that
lead to secretion of some proinflammatory cytokines including this complex mainly accumulated in the mitochondria and was
CXCL10 and IL1b from A549 cells. Mechanistic studies illu- partially localised in the ER, and the photo-triggered ROS may
strated that complex 4-31 induced ROS accumulation in mito- result in oxidative damage to intracellular targets such as
chondria, resulting in the mitophagy-mediated release of a proteins and nucleic acids, thus inducing the ICD process.264
variety of DAMPs, eventually triggering ICD. Moreover, when Very recently, Zou and Liang et al. discovered an ER stress-
co-cultured with human immune cells and A549 cells, complex inducing bisNHC-iridium(III) complex 4-34 as a new ICD
4-31 tremendously increased the immunogenicity of tumor inducer.265 Importantly, by structural functionalization of this
cells, resulting in enhanced phagocytosis of A549 cells by complex, a clickable and photoaffinity probe 4-35 (Fig. 38(a))
macrophages.262 was rationally developed for target identification. Conse-
Cyclo-metalated iridium(III) complexes also hold great quently, the binding immunoglobulin protein (BIP), a vital
potential as ICD inducers. The first iridium(III) complex-based protein for ER homeostasis regulation, was successfully
ICD inducer 4-32 was reported recently by the Chao group.263 screened out and validated as an important target during the
Complex 4-32 was tethered to a bis(2-chloroethyl)-azane deri- ICD process. Furthermore, BIP destabilisation was also consis-
vative, the action site of the ICD inducer cyclophosphamide tently observed for other clinic-related ICD inducers, including
(Fig. 38(a)). This complex was specifically localised in the ER of oxaliplatin, ruthenium(II)-based KP1339, and mitoxantrone,
A549 cells, where complex 4-32 induced ER stress and ROS, confirming the crucial role of BIP in ICD stimulation.265
consequently causing CTR exposure as well as ATP and HMGB1 Very recently, our group reported a cyclo-metalated
release. As expected, the reference complex without the bis(2- platinum(IV)-terthiophene complex 4-36 (Fig. 38(a)) that can
chloroethyl)-azane derivative was unable to induce those ICD simultaneously perturb intracellular redox and Zn2+ homeos-
hallmarks. Importantly, the vaccination of immunocompetent tasis to activate pyroptosis and immune responses including
mice with 4-32-treated dying cells caused the activation of CD8+ ICD, DC maturation and T cell tumor-infiltration.249 As indi-
T cells and the depletion of Foxp3+ T cells, finally leading to cated in the above-mentioned section, the rhenium(I) pyropto-
long-lasting anti-tumor immunity through in vivo ICD induc- sis inducer 2-60 and the iridium(III) ferroptosis inducer 3-33
tion. Brabec and Ruiz et al. prepared a photoactivated also feature ICD stimulation property.109,245 At present, orga-
iridium(III) complex 4-33 (Fig. 38(a)).264 Upon blue light irradia- nometallic ICD inducers are still rare, and most of them were
tion, this complex exhibited a strong enhancement in cytotoxi- developed during the last three years and are mainly based on
city with high phototoxicity indices (43–100) in both normoxia platinum(II),258,260 gold(I)261,262 and iridium(III).245,263–265 In
and hypoxia and triggered the secretion of ICD-characteristic fact, since ICD is a relatively nascent pathway, the ICD
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induction ability of previously developed organometallic com- for ICD property investigations. Therefore, the rational design
plexes may be neglected. For instance, a ruthenium(II)–arene of metal complexes that can induce the above-mentioned
anti-tumor drug candidate 4-37 (Fig. 38(a)) was freshly identi- effects may be a way for the rational design of ICD inducers
fied as an ICD inducer.266 In addition to ICD induction, this in the future.
complex exhibits anti-tumor efficacy in a synergistic fashion As discussed above, nine cell death pathways have been
together with specific plectin inhibition.267 Inspired by this, we identified that can be efficiently induced by organometallic
presume that the ICD induction ability of many existing anti- complexes. Nevertheless, there are still some cell death modes
tumor organometallic complexes still remains to be explored. caused by organometallics that cannot be clearly defined based
From our point of view, metal complexes may have advantages on the current knowledge.268 Efforts on deep elucidation of cell
in inducing ICD because (1) we found that metal compounds death pathways and exploration of novel cell death modes are
distributed on the cell membrane to trigger cell membrane still ongoing. It is worth noting that the interplay between
rupture or localised in the nucleus to cause DNA damage can different cell death signalling pathways should not be over-
readily induce ICD;109,251 (2) many metal compounds are able looked, and in some cases, more than one cell death pathway
to induce ER stress in tumor cells, which is a key progenitor of can be induced by a single molecule.
ICD;254 and (3) metal compounds are prone to undergo intra- Since apoptosis is a non-inflammatory cell death form and
cellular redox reactions and induce ROS to perturb redox mainly causes the ‘‘exact’’ cell death without influencing sur-
homeostasis and trigger downstream events such as ICD.255 rounding cells, the pro-inflammatory cell death pathways may
Current metal-based ICD inducers cover a variety of structures act as more efficient anti-tumor cell death modes as they are
with different metals and ligands, and a clear structure–activity able to trigger inflammatory reactions and simultaneously lead
relationship is yet to be established. The general ICD mecha- to not just individual cell but multiple cell death. In fact,
nism from a biological angle is briefly summarised in increasing evidence has revealed that certain cell death modes
Fig. 38(b). It is worth noting that besides the well-recognised such as autophagy, necroptosis, ferroptosis, pyroptosis, and
ICD hallmarks of CRT translocation, ATP secretion, and ICD can exert synergistic anti-tumor immunity.269 In the past,
HMGB1 release, intracellular ROS generation and ER stress organometallic complexes have demonstrated that they can
may serve as the initiators for ICD. Moreover, BIP inhibition, efficiently induce a variety of both non-inflammatory and pro-
HSP90 activation, metal homeostasis perturbation, and proin- inflammatory cell death pathways, indicative of their great
flammatory cytokine secretion could provide additional clues potential as anti-tumor agents. To facilitate the rational design
Table 3 Morphological and biochemical features of various cell death pathways induced by organometallic compounds
Cell death
mode Morphological features Biochemical features Organometallic type Metal Ref.
Apoptosis Cell shrinkage, membrane blebbing, chro-
TNFSF activation, BH3-only protein Metal carbonyl, cyclo- Re, 211–215
matin condensation, apoptotic body upregulation, Bcl-2 downregulation, metalated complex, Pd, Ir
formation Bax and Bak upregulation, caspase metal carbene
upregulation
Paraptosis Massive cytoplasmic vacuolization, mito- MAPK upregulation, UPS impairment, Cyclo-metalated Ir, Ti, 95 and 217–220
chondrial swelling and ER stress CHOP overexpression complex Re
Autophagy Autophagosome formation, autophagosome– mTOR inhibition, LC3-I to LC3-II Cyclo-metalated Ir, 75 and 222–225
lysosome fusion conversion complex, metal carbo- Re,
nyl, metal arene Ru
Oncosis Cell and organelle swelling, mitochondrial Cell membrane ionic pump impair- Cyclo-metalated Ir, 227–229
condensation, nuclear chromatin clumping, ment, Bcl-2 : Bax ratio increase, por- complex, metal arene Ru,
cytoplasmic vacuolization, plasma membrane imin activation, calpain 1 upregulation Os
blebbing and permeability increasing, cytos-
keletal collapse
Necrosis Cytoplasmic and organelle swelling, cell RIP3 upregulation, LDH leakage Cyclo-metalated Ir, Re 231 and 238
membrane rupture and cellular content complex, metal
release carbonyl
Necroptosis Cell swelling, pore formation on the cell RIPK1 and RIPK3 upregulation, MLKL Cyclo-metalated Ru 239
membrane, plasma membrane rupture phosphorylation complex
Ferroptosis Cell swelling, plasma membrane collapse, GPX4 inhibition, LPO and iron accu- Cyclo-metalated Ir, Pt 243–246
intact nuclei, mitochondrial shrinkage, mito- mulation, GSH depletion complex
chondrial cristae reduction or disappearance,
outer mitochondrial membrane rupture
Pyroptosis Cell swelling, pore formation on cell mem- Caspase 1/4/5/11 activation, GSDMD Metal carbonyl Re, 109 and 249
branes, large bubbles blowing from the cleavage, GPX4 inhibition, IL-1b and Pt
plasma membrane, plasma membrane lysis, IL-18 release
chromatin fragmentation
ICD ER stress and extracellular DAMP release CRT translocation, ATP and HMGB1 Cyclo-metalated Pt, 109,245,249,258
release, BIP inhibition, HSP90 complex, metal car- Au, and 260–266
activation bene, metal arene, Ru,
metal carbonyl Ir, Re
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and identification of certain cell death-triggering compounds, envision that this research field will flourish in the near future.
the morphological and biochemical features of each cell death Immune homeostasis is currently experiencing a blooming
mode are briefly summarised in Table 3, from which specific research stage. Although a series of organometallic compounds
biological factors during the cell death process may be targeted that can activate the anti-cancer immune response have been
to induce certain cell death. In future anti-cancer drug devel- reported, further understanding of the molecular mechanisms
opment, triggering alternative forms of the cell death pathway of immune intervention by organometallic compounds is
could be a promising therapeutic strategy for achieving better required. Apart from the above-mentioned modes of home-
anti-tumor efficacy. ostasis, other homeostatic pathways such as biomolecular

condensation and anion homeostasis could also serve as tar-
gets of organometallic compounds in cancer chemotherapy.
5. Conclusion and future perspectives Once cellular homeostasis is perturbed in cancer cells,
various cell death pathways can be activated. Although apop-
The development of metal-based anti-tumor drugs is a bur- tosis is the most commonly reported cell death pathway
geoning research field since the clinical success of cisplatin and induced by organometallic compounds, there is increasing
its analogues has proved the potential of metal-based com- evidence that organometallic compounds can also activate
pounds for anti-tumor therapeutic applications. However, clas- other types of cell death pathways in tumors, such as ICD,
sical platinum-based anti-tumor drugs still exhibit serious ferroptosis, and pyroptosis. The ability of organometallic com-
problems, such as high general toxicity and drug resistance. pounds to activate multiple cell death pathways could substan-
Therefore, there is an urgent need to develop novel metal-based tially improve their anti-tumor efficacy because (i) they hold the
anti-tumor drugs that have high tumor selectivity and novel potential to alleviate apoptosis-related drug resistance; and (ii)
mechanisms of action. Owing to the unique chemical and certain cell death modes could further trigger inflammatory
biological properties, organometallics are a promising class of reactions and immune responses, thus simultaneously enhan-
anti-tumor therapeutic and diagnostic agents, which can be cing anti-tumor efficacy through activation of the endogenous
designed with enhanced tumor selectivity and unique modes immune system. Inspired by new cell death pathways such as
of action. This review describes recent advances in the cuproptosis207 and calcicoptosis,270 we envision that these new
development of anti-tumor organometallic compounds, espe- and other unidentified cell death modes could also serve as
cially focusing on their mode of action from three aspects: targets of organometallic compounds for cancer treatment in
cancer-specific biomolecule targeting, cellular homeostasis the future.
perturbation, and activation of various cell death pathways in Although substantial progress has been made in delineating
cancer cells. the mode of action of organometallic compounds, much
Since tumors require a continuous source of energy and remains to be learned about their anti-tumor structure–reactiv-
possess rapid growth rate and metastatic potential, some ity relationship. In particular, it is still a challenge to design an
biomolecules produced in tumor cells such as cell receptors, organometallic compound to activate specific cell death path-
membrane transporters, intracellular enzymes, and certain ways at present, since the cell death modes often involve
nucleic acids are significantly elevated, thereby serving as sophisticated networks of signalling pathways. Based on recent
cancer-specific targets for rational design of anti-tumor drugs. research progress in bio-organometallic chemistry, we summar-
An array of organometallic compounds has been synthesised ise the current anti-tumor strategy as a three-layer hierarchical
via the introduction of pharmacological ligands or functional network (Fig. 39). At present, we can rationally design com-
groups to the metal centre to achieve selective targeting pounds with high specificity towards certain biomolecules on
towards tumor cells. Such biomolecular targeting can further layer 1. Future efforts should be made to develop novel orga-
perturb cancer cell metabolism and the tumor microenviron- nometallic compounds that target certain tumor homeostasis
ment, including energy supply, free radical production, metal (layer 2) or cell death pathways (layer 3). Since the three layers
metabolism, and immune surveillance. Therefore, organome- of anti-tumor ‘‘targets’’ are closely related to each other, further
tallic compounds reported to date usually have the capability to elucidation of the relationship among these three-layer ‘‘tar-
intervene in tumor energy/redox/metal/immune homeostatic gets’’ is highly needed.
pathways. Over the past decade, extensive efforts have been The application of organometallic compounds with novel
dedicated to studying energy and redox homeostasis in cancer anti-tumor mechanisms could help to overcome the difficulties
cells. However, less attention has been paid to intracellular associated with conventional chemotherapies. In the mean-
metal homeostasis in cancer cells. A series of endogenous time, other therapeutic strategies, such as combination
metal ions such as zinc and copper play essential roles in therapy,271 nanomedicine272 and carrier-mediated drug
cancer progression and metastasis. Therefore, perturbation of delivery,273 could also be considered to further improve anti-
intracellular metal homeostasis in cancer cells via organome- tumor efficacy. Therefore, collaboration among scientists, hos-
tallic compounds could be a potential strategy for cancer pitals, and pharmaceutical companies is encouraged to push
treatment and merits further investigation. In particular, recent forward those anti-tumor organometallic compounds from the
advances in multi-omics techniques could significantly pro- bench side to the bedside, which may cost tremendous
mote research on intracellular metal homeostasis, and we resources but is worthwhile to try. We envision that successful
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Fig. 39 General action mechanisms of anti-tumor organometallic complexes.
clinical translation of anti-tumor organometallic compounds is NSCLC Non-small cell lung cancer
a difficult but attainable goal in the future. G4 DNA G-Quadruplex DNA
PTK-7 Protein tyrosine kinase 7
GSK-3 Glycogen synthase kinase 3
Author contributions CDKs Cyclin-dependent kinases
ROS Reactive oxygen species
K. P. and Y. Z. contributed equally to this work. Z.-W. M., W. X.
HCD Higher energy collision dissociation
and K. P. conceived the scope of the review and drafted the
ER Endoplasmic reticulum
initial idea. K. P. and Y. Z. wrote the manuscript, and Z.-W. M.
ASNS Asparagine synthetase
and W. X. revised and edited the manuscript to the final
AIE Aggregation-induced emission
version. All the authors read, revised, and approved the final
KDM5A Lysine-specific demethylase 5A
version.
HDACs Histone deacetylases
SAHA Suberoylanilide hydroxamic acid
JAHA Jay Amin hydroxamic acid
Abbreviations
GSTs Glutathione S-transferases
ICD Immunogenic cell death EA Ethacrynic acid
Cp Cyclopentadienyl NBDHEX 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol
NHC N-Heterocyclic carbene NSAIDs Non-steroidal anti-inflammatory drugs
GLUTs Glucose transporters COX Cyclooxygenases
TrxR Thioredoxin reductase PARP-1 Poly(ADP-ribose) polymerase 1
SMVT Sodium-dependent multivitamin transporter APO 3-Aza-5[H]-phenanthridin-6-one
ABC Adenosine triphosphate-binding cassette 3-AB 3-Aminobenzamide
Cp* Pentamethylcyclopentadiene CA IX Carbonic anhydrase IX
GPCR G-Protein-coupled receptor PDT Photodynamic therapy
DOR d-Opiate receptor CHO Chinese hamster ovary
MOR m-Opiate receptor MDCK Madin-Darby canine kidney
GRPR Gastrin-releasing peptide receptor HIF-1a Hypoxia inducible factor-1a
RGD Arg–Gly–Asp FLIM Fluorescence lifetime imaging microscopy
HER2 Human epidermal growth factor receptor 2 tRNA Transfer RNA
EGFR Epidermal growth factor receptors mRNA Messenger RNA
RTK Receptor tyrosine kinase ct-DNA Calf thymus DNA
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DFT Density functional theory LDH Lactate dehydrogenase

ATP Adenosine triphosphate RIP3 Receptor-interacting proteins 3
OXPHOS Oxidative phosphorylation RIPK Receptor-interacting protein kinase
DCA Dichloroacetate MLKL Mixed linkage kinase domain-like protein
PDK Pyruvate dehydrogenase kinase ZBP1 Z-DNA binding protein 1
MMP Mitochondrial membrane potential GPX4 Glutathione peroxidase 4
ETC Electron transport chain HMOX1 Heme oxygenase 1
mtDNA Mitochondrial DNA LPO Lipid peroxide

nDNA Nuclear DNA GSDMD Gasdermin D
CIN Chromosomal instability GSDMD-N Gasdermin D N-terminal domain
AMPK 5 0 -Adenosine monophosphate-activated protein cGAS Cyclic GMP-AMP synthase
kinase STING Stimulator of interferon genes
GSH Glutathione cGAMP Cyclic GMP–AMP
TNBC Triple-negative breast cancer DAMPs Damage-associated molecular patterns
SOD Superoxide dismutases NCCD Nomenclature Committee on Cell Death
RNS Nitrogen species CRT Ca2+ binding chaperon protein calreticulin
NADH Nicotinamide adenine dinucleotide HMGB1 High-mobility group box 1
DC Dendritic cell TLRs Toll-like receptors
CTL Cytotoxic T lymphocyte PERK Protein kinase RNA-like endoplasmic reticulum
NK Natural killer kinase
Tregs Regulatory T lymphocytes UPR Unfolded protein response
MDSCs Myeloid-derived suppressor cells BIP Binding immunoglobulin protein
TIME Tumor immune microenvironment
CAFs Cancer associated fibroblasts
IDO Indoleamine 2,3-dioxygenase Conflicts of interest
TAM Tumor-associated macrophage
NO Nitric oxide There are no conflicts to declare.
iNOS Inducible nitric oxide synthase
LPS Lipopolysaccharide
NF-kB Nuclear factor-kB Acknowledgements
IL Interleukin This work was financially supported by the National Key R&D
TNF-a Tumor necrosis factor a Program of China (2022YFB3804502), National Natural Science
a-kG a-Ketoglutarate Foundation of China (22293053, 21837006, 22022706,
5mC 5-Methylcytosine 22077142, 22107124 and 91953117), Guangdong Basic and
m 6A N6-Methyladenosine Applied Basic Research Foundation (2022A1515111089 and
SAM S-Adenosylmethionine 2023A1515010625) and Fundamental Research Funds for the
SAH S-Adenosylhomocysteine Central Universities.
TNFSF Tumor necrosis factor superfamily
Bcl-2 B-Cell lymphoma 2
DISC Death-inducing signal complex References
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Organometallic Anti-Tumor Agents: Targeting From Biomolecules To Dynamic Bioprocesses

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Organometallic Anti-Tumor Agents: Targeting From Biomolecules To Dynamic Bioprocesses

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Chem Soc Rev

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Organometallic anti-tumor agents: targeting from

Kun Peng, † Yue Zheng, † Wei Xia * and Zong-Wan Mao *

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Wei Xia received his bachelor’s Zong-Wan Mao earned his

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Fig. 1 Important milestones in the history of the development of bio-organometallic complexes.

cellular homeostasis perturbation by organometallic com-

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multivitamin transporter (SMVT) were used to examine the

non-biotinylated compound and the organic biotin ligand.29

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simulation for complex 2-18 with the aromatase enzyme indi-

in vivo anti-tumor activities.53

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MB-231 cells was enhanced under hypoxia, which is an impor-

hypoxia-inducible factor-1a (HIF-1a) plays an essential role.

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targeting complexes is possibly because tumor cells need more

Fig. 18 (a) Chemical structures of tRNA-targeted organometallic com-

Biomolecular target Organometallic type Metal Bio-functional group Ref.

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iridium(III) complex 3-3 that can efficiently disturb tumor cell

treatment, the mitochondrion-encoded subunits I, II, and III of

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Fig. 22 (a) Chemical structures of organometallic complexes 3-8 and 3-9

induced glucose metabolism reprogramming under low glu-

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Although current metal homeostasis studies mostly focus on

encouraged for supplementation.

3.4 Immune homeostasis

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Table 2 Representative examples of bioprocesses intervened by organometallic complexes

NADH oxidation metal Cp, metal arene 164

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the lysosome through fusing with the lysosome; (3) as a result,

phosphatidylinositol 3-kinase (PI3k), mammalian target of

4.2 Autophagy and oncosis

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induced and generally regarded as biochemical hallmarks of

nuclear high-mobility group box 1 (HMGB1) protein is exported

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