Coordination Chemistry Reviews 436 (2021) 213849

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Coordination Chemistry Reviews

journal homepage: www.elsevier.com/locate/ccr

Review

Biological properties of ruthenium(II)/(III) complexes with flavonoids

as ligands
Magdalena Małecka a,⇑, Anna Skoczyńska b,c, David M. Goodman d, Christian G. Hartinger d,
Elzbieta Budzisz b,⇑
a
Department of Physical Chemistry, Faculty of Chemistry University of Lodz, Pomorska 163/165, 90-236 Łódź, Poland
b
Cosmetic Row Materials Chemistry, Faculty of Pharmacy, Medical University of Łódź, Muszynskiego 1, 91-419, Poland
c
Department of Pharmacology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jagiellonska 4, 41-200 Sosnowiec, Poland
d
University of Auckland, School of Chemical Sciences, Private Bag 92019, Auckland 1142, New Zealand

a r t i c l e i n f o a b s t r a c t

Article history: This review highlights the progress in the development of ruthenium(II)/(III) complexes with flavone
Received 4 November 2020 derivatives as potential therapeutic agents. We focused on natural hydroxyflavone derivatives and their
Received in revised form 3 February 2021 synthetic amino analogues as ligands in ruthenium(II)/(III) complexes which demonstrate antimicrobial,
Accepted 4 February 2021
antitumor activity and/or enzyme inhibition. Some enzymes targeted by flavone derivatives are impor-
Available online 8 March 2021
tant for the development and progression of cancer cells which underpins the design concept for the
Ru complexes as multitargeted compounds consisting of a bioactive ligand and a ruthenium center.
Keywords:
Ó 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://
Flavonoids
Ruthenium(II)/(III) complexes
creativecommons.org/licenses/by/4.0/).
Antitumor activity

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Therapeutic properties of flavonoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Biological properties of Ru(II)/(III) complexes with flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.1. Ruthenium compounds of O-donor flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.1.1. Ruthenium coordination compounds – From mono- to dinuclear anticancer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.1.2. Bioorganoruthenium chemistry: Ru(g6-arene) complexes of O-donor flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.2. Ru(II)/(III) complexes of aminoflavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

1. Introduction complexes containing chromone, coumarin and flavonoid ligands

For several years our scientific efforts have been focused on
metal complexes containing flavone-derived ligands and exploit-
ing their interesting chemical and biological properties [1]. Metal
⇑ Corresponding authors.
E-mail addresses: magdalena.malecka@chemia.uni.lodz.pl
elzbieta.budzisz@umed.lodz.pl (E. Budzisz).
have demonstrable activity against leukemia, lung, cervical, and
melanoma cancer cell lines [2–5] as well as being efficacious
against Huntington’s [6–8], b-thalassemia [9–11], heart diseases
and diabetes mellitus [12–15]. Plant-synthesized flavones [16]
are biologically interesting molecules, due to the structure-
dependent medicinal and biological properties [17], which include
(M. Małecka), antioxidant [18], antimicrobial [19], antiviral [20], antibacterial
[20], antidiabetic, and anti-inflammatory activity, in addition to

https://doi.org/10.1016/j.ccr.2021.213849
0010-8545/Ó 2021 The Authors. Published by Elsevier B.V.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
metal chelation [16]. Flavones are polyphenolic compounds with a
general structure consisting of two benzene rings (A and B) and a
heterocyclic pyran ring (C) fused to ring A. This compound class
is divided into six subclasses, i.e. flavonols, flavanols, flavones, fla-
vanones, isoflavones, and anthocyanidins [21], with the differences
between the subclasses arising from the substitution position of
ring B with C, the saturation and substitution of ring B, and the
functionalization pattern of the rings through hydroxylation and
glycosylation [22].
The biological activity of Ru complexes has been widely inves-
tigated. Ruthenium(III) complexes have shown remarkable antitu-
mor activity with various advantages over traditional platinum
drugs, including potent efficacy, low toxicity and less drug resis-
tance [23–25], while Ru(II) compounds, in particular, organo-Ru
compounds have demonstrated very different biological properties
including in in vivo studies [26,27].
The combination of Ru(II)/(III) complexes with bioactive flavone
ligands can act synergistically resulting in superior biological activ-
ity. Ruthenium(II)-arene complexes with high activity towards
both primary and secondary metastatic tumors have been reported
[28,29]. The in vivo antioxidant properties of flavonoids may be
modulated by metal coordination and thereby affect enzyme inhi-
bitory activity. Similar observations have been made for other
bioactive ligand–metal center complexes, resulting in multimodal
anticancer agents [1,30]. The modes of action of multimodal anti-
cancer agents is influenced by complex stability and as such, Ru
compounds were compared to selected Fe derivatives, due to oxi-
dation state and structural similarities [31]. Herein, we summarize
comprehensively the effect of coordination of flavonoid ligands to
Ru(II) and Ru(III) centers on their biological activities [30].
2. Therapeutic properties of flavonoids
Flavonoids are known for their interesting bioactivity profiles
which make them useful for medical and pharmaceutical applica-
tions. The development of flavonoids as potential anticancer agents
is the most widely studied application with further evidence
demonstrating efficacy as antioxidant, antiinflammatory, antiasth-
matic, antimicrobial and antidiabetic agents. These indications
have been explored through enzyme inhibition and other protein
interactions such as the molecular docking between quercetin 1
and inducible nitric oxide synthase (iNOS).
The anticancer activity of flavonoids arises from the targeting of
kinases, apoptotic proteins, and growth factors thus impacting cell
growth, matrix metalloproteinase (MMP) secretion and angiogen-
esis [32]. Some of the enzymes targeted are protein kinase C
(PKC), epidermal growth factor receptor (EGFR), and focal adhesion
kinase (FAK), which are important for the development and pro-
gression of cancer. Quercetin 1 (Fig. 1), a polyhydroxylated flavo-
noid, is the most active inhibitor of PKC [33–35] with Ferriola
et al. [36] showing that quercetin 1, fisetin 2 and luteolin 3 inhib-
ited rat brain PKC through blocking the catalytic unit of PKC at the
ATP binding site. Quercetin 1 and luteolin 3 decreased MMP-2 and
MMP-9 activity in cancer cells such as A549, A431, and MiaPaCa-2
[37]. It was found that quercetin 1 interrupts the elongation of
telomeric ends [38]. Luteolin 3 induced apoptosis and caused
oligonucleosomal DNA cleavage, cytoplasmic blebbing and PARP
(poly[ADP-ribose] polymerase 1) degradation in A431 epidermoid
carcinoma cells and in pancreatic cancer MiaPaCa-2 at 15-25 mM
[39]. According to Akiyama et al. [40] isoflavone 4 and genistein
5 are specific inhibitors of protein tyrosine kinase (PTK) and 5
exhibited antiproliferative activity against HL-60 and K-562
human cells while 4 suppressed EGFR, and tyrosine kinase activity
in A431 human cells [41]. Within eight hours, compound 5 induced
apoptosis in HL-60 cells [42], due to the inhibition of EGFR, TGF-b
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Coordination Chemistry Reviews 436 (2021) 213849
(transforming growth factor beta) and bFGF (basic fibroblast
growth factor). Isoflavone 4 inhibited the growth of breast cancer
MCF-7 and MDA-MB-468 cells, which are estrogen receptor-
negative, as well as of estrogen receptor-positive MCF-7-D40 cells
with IC50 values from 6.5 to 12 mg/ml [18]. Polymethoxylated citrus
flavones, like tangeretin 6 and nobiletin 7, inhibited cell growth in
human squamous cell carcinoma and gliosarcoma cells at concen-
trations ranging from 5 to 20 mM [43,44] with no activity against
human diploid fibroblast-like lung cells (CC1135) [45]. Tangeretin
6 caused apoptosis in HL-60 leukemia cells at concentrations >
2.7 mM. Additionally, the flavanols, which are tea polyphenols such
as epicatechin (EC) 8, epicatechin gallate (ECG) 9, epigallocatechin
(EGC) 10, and epigallocatechin gallate (EGCG) 11 [46], suppressed
human cancer cell growth [47] with EGCG 11 being shown to also
inhibit the metastasis of B16 melanoma cells. These tea polyphe-
nols target the Bcl-2 family proteins thus inhibiting their antiapop-
totic activity. Shukla and Gupta [48] observed that apigenin 12
induced apoptosis in prostate cancer cells DU145. (+)-Catechin
13 can bind to laminin, which is involved in metastasis of malig-
nant tumor cells [49]. Bagli et al. [50] found that fisetin 2, luteolin
3, apigenin 12, 3–hydroxyflavone 14, 30 ,40 -dihydroxyflavone 15,
and 20 ,30 -dihydroxyflavone 16 inhibited the in vitro angiogenesis
of tumor cells. Flavonoids obtained from Trichosanthe kirilowii
extract, such as isorhamnetin 17, genkwanin 18 and acacetin 19,
induced cell cycle arrests, apoptosis, and autophagy in human
breast cancer cells. In addition to PKC and PTK, flavonoids can inhi-
bit other kinases including phosphoinositol kinase, phosphatidyli-
nositol kinase, or cyclin-dependent kinase-4 [51,52]. Moreover,
flavonoids can inhibit transcription factors like NFjB [53], involved
in the regulation of inflammatory chemokines and cytokines [54]
with additional potential to inhibit cyclooxygenase (COX) and
lipoxygenase (LOX) enzymes which catalyze the arachidonic acid
metabolism and inhibit inflammatory mediators [55]. Inhibition
of the biosynthesis of such mediators can result from a lower activ-
ity of enzymes such as PLA2 (phospholipases A2) [56,57], LOX [58]
or COX [59]. Furthermore, flavonoids modulate the impact of tran-
scription factors such as GATA-3 and activate transcription factor 6
(STAT-6) [60,61].
Molecular docking studies can play an important role in drug
design [62,63], aiming to predict protein target-ligand binding
modes and related affinities [64]. Successful docking methods
explore three-dimensional spaces effectively and the score func-
tion rates potential complementarity to binding sites [65]. Several
molecular docking studies have been conducted to support inves-
tigations on the targets of flavonoids [66–68], including cyclin-
dependent kinases (CDK) with 8-CF (8-chloroflavone) being docked
with CDK6 with binding energies between 13.22 and 9.47 kcal/-
mol and hydrophobic and hydrogen bonding interactions
observed. These results validated the hypothesis of CDK6 inhibi-
tion by 8-CF and supported the experimental results which showed
that 8-CF induced cell cycle arrest in the G1 phase caused by CDK6
inhibition [69]. Furthermore, Ding et al. [70] used molecular dock-
ing supported by molecular dynamics (MD) simulations to derive
structure–activity relationships for hemoglobin binding by con-
firming the stability of the molecular docking results (entry code
2DN1, Fig. 2) [71]. Both methods were in agreement demonstrating
significant conformational changes upon flavonoid binding except
for a small rotation of the hydroxyl group in galangin 20, resulting
in different non-covalent interactions.
In case of the novel aurora kinase inhibitor luteolin 3, molecular
docking studies at the ATP-binding site of aurora kinase (PDB
ID:1OL6) [72] indicated stabilization of the inhibitor-protein com-
plex through a bidentate H-bonding pattern between 3 and Ala213
(Fig. 3) concluding that the introduction of a hydroxyl group at
position 5 could increase the bioactivity [73].
M. Małecka, A. Skoczyńska, D.M. Goodman et al. Coordination Chemistry Reviews 436 (2021) 213849

Fig. 1. Structures of compounds listed in the publication.

Studies by Kartasasmita and co-workers [74] investigated inhi- results for iNOS (PDB ID: 1M9T) [75] showed hydrogen bonding
bitory activities of the flavonoids kaempferol 26, quercetin 1, api- between the amide groups of Gly365 and Trp366 and the respec-
genin 12, and primuletin 35 against (iNOS), which catalyzes the tive flavonoids (Fig. 4). These studies demonstrated that the 4-
production of nitric oxide from L-arginine. The molecular docking carbonyl group and the planar fused bicyclic region are essential

3
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
Fig. 1 (continued)
structural features for the binding. Additionally, there was correla-
tion between the experimental IC50 values and calculated binding
energies (DG) (R2 = 0.686).
As mentioned above, flavonoids are LOX inhibitors [55] and its
inhibition may be a strategy to prevent carcinogenesis [76–78]. As
secondary metabolites commonly act as negative feedback inhibi-
tors, the secondary metabolites of the human isozyme 5-LOX were
screened for pharmacokinetic properties by molecular docking
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Coordination Chemistry Reviews 436 (2021) 213849
studies to develop inhibitors of 5-LOX [79]. The studies of Singh
et al. [80] revealed that only six flavonoids of the 26 compounds
selected were found to dock successfully with 5-LOX with the most
potent inhibitors, genkwanin 18, baicalein 22, chrysin 23, galangin
20 and velutin 24, being compared to the known 5-LOX inhibitor
zileuton [81]. This study with further analyses suggested velutin
24 as the most promising lead compound for anticancer activity
through the inhibition of 5-LOX (Fig. 4) [82].
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
Fig. 1 (continued)
Molecular docking studies of the E6 onco-protein, a subcellular
target for human papillomavirus (HPV) therapeutics [83], with the
herbal flavonoids apigenin 12 and silymarin [84] found that sily-
marin binds through the formation of hydrogen bonds to Tyr32
and Arg55 and is a suitable candidate for further development.
Another secondary metabolite, i.e., apigenin-7-O-rhamnosyl-6-
C-glucoside and its derivatives, obtained from the leaves of Ery-
thrina crista-galli, were investigated by molecular docking [85]
for binding to the human estrogen receptor R (ERR, PDB ID:
1A52) [86]. Interactions to Arg394, Glu353 and His524 were iden-
tified to be similar to how 17b-estradiol interacted with the active
site, however, with a higher correlation factor. The lead compound
apigenin-7-O-rhamnosyl-6-C-glucoside formed additional hydro-
gen bonds to amino acids in the pocket.
Meta-analyses have shown that both individual and total flavo-
noid consumption reduce the risk of numerous cancers [87]. This
may be due to the potent antioxidant properties of flavonoids with
these properties being dependent on the structure, specific pattern
of substitution and presence of phenolic hydrogens. Flavonoids
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Coordination Chemistry Reviews 436 (2021) 213849
inhibit free radical production and scavenge ROS (Reactive Oxygen
Species) and RNS (Reactive Nitrogen Species) [88,89]. Additionally,
flavonoids inhibit cAMP phosphodiesterase activity responsible for
the regulation of cell function during inflammation by blocking
cAMP degradation and prolonging cAMP signaling [90,91]. Further-
more, flavonoids inhibit proinflammatory cytokine and chemokine
production in neutrophils, mast cells and other immune cells [92–
94], in addition to inhibiting or decreasing the activation of
immune cells involved in inflammation processes such as mono-
cytes [95,96].
Asthma is characterized by chronic inflammation of the respira-
tory tract, and can be improved by flavones, flavonols, anthocyani-
dins, and isoflavones through their anti-inflammatory properties.
Luteolin 3 caused less prostaglandin D2 and histamine release
from human mast cells [97] while tetramethoxyluteolin (methlut)
25 has potential to stop inflammatory mediators from human mast
cells. Quercetin 1, was found to inhibit IL-4 and IL-5 cytokines [98]
with kaempferol 26 being shown to block degranulation of eosino-
phils in a murine lung tissue model [60,91,99]. The reduction of
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
Fig. 2. Results of molecular docking calculations for galangin 20 (orange) into
hemoglobin. The apoprotein is shown as light cyan, and the average position of
protein as light pink. The average conformation for flavone is drawn in yellow.
Reproduced with permission from ref. [70]. Ó RSC 2016.
Fig. 3. Schematic predicted binding modes of luteolin 3 in the ATP active site of
aurora kinase (PDB ID 1OL6).
allergic inflammation and lessened release of cytokines was medi-
ated through mechanisms involving the blockade of NFjB [67]. The
anti-inflammatory properties of genistein 5 are exhibited through
the inhibition of proinflammatory cytokine release from mast cells
and decreased airway inflammation through the inhibition of tran-
scription factors GATA-3 and STAT-6 [60]. Cyanidin 27, an antho-
cyanidin, attenuated inflammation induced by Th17 in a mouse
model for severe asthma [100]. Research conducted on Japanese
women proved that eating flavonoid rich soybean can diminish
the prevalence of allergic rhinitis [101].
Flavonoids might prevent cardiovascular disease due to their
anti-inflammatory, antioxidative and vasodilatory properties by
increasing HDL (High Density Lipoprotein) concentration [102]. A
recent study showed strong evidence that consumption of flavo-
noids rich foods corresponded with a diminished risk of mortality
due to cardiovascular diseases [103] with significantly decreased
cholesterol accumulation due to the impact of 1, indicated by the
presence of quercetin 1 metabolites in rabbit aortas [104]. Querce-
tin 1 inhibited the maturation of dendritic cells in mice [105] and
activated macrophages in inflamed arteries are also potential tar-
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Coordination Chemistry Reviews 436 (2021) 213849
gets [106]. Administration of quercetin 1 in rats for 14 days
resulted in diminished oxidative stress, reduced inflammation,
improved heart architecture and can relieve or eliminate symp-
toms associated with heat stroke [107]. Similarly, isoflavone 4
and puerarin 28 have been shown to suppress atherosclerosis in
rabbits [108]. It was found in different animal models that the fla-
vone baicalin 22 protected the cardiovascular system by improving
myocardial hypertrophy, cardiac dysfunction, and decreasing
apoptosis in cardiac tissue [109]. Additionally, through the pres-
ence of hydroxyl groups, flavonoids, such as chrysin 23, found in
honey and passionflower, have been shown to inhibit platelet acti-
vation and prevent clot formation [110].
Apigenin 12, galangin 20, isoflavones, flavanones, flavone and
flavonol and other glycosides possess antibacterial activity
[21,111] by inactivating microbial adhesins, enzymes, and trans-
port proteins [112,113]. Robinetin 29, myricetin 30, and ()-
epigallocatechin 31 were shown to inhibit replication of DNA from
Proteus vulgaris with other studies demonstrating that 1, 12 and
3,6,7,30 ,40 -pentahydroxyflavone 32 affect Escherichia coli DNA gyr-
ase activity [114]. Additional antibacterial properties were found
for naringenin 33 and sophoraflavanone G 34, which are
particularly active towards Streptococci and methicillin-resistant
Staphylococcus aureus (MRSA). According to Osawa et al. [115]
5-hydroxyflavanones 35 and 5-hydroxyisoflavanones substituted
with one, two or three hydroxyl groups at the 7, 20 or 40 positions
stopped the growth of both Streptococcus sobrinus and Streptococ-
cus mutans. Similarly, Haraguchi et al. [116] studied flavonoids
licochalcones A 36 and C 36a, obtained from Glycyrrhiza inflata,
were active against Micrococcus luteus and Staphylococcus aureus.
Many derivatives mirror the antibacterial properties of flavonoids
derived from edible and medicinal plants [117–119].
The antidiabetic properties of flavonoids are due to the induc-
tion of insulin release and activation of pancreatic b-cells [120]
with 11 causing a hypoglycemic effect by inhibition of glucose syn-
thesis in hepatocytes. Kaempferol 26 can reduce oxidative stress in
the endoplasmic reticulum (ER) giving it therapeutic potential
[121,122]. Flavonoids isolated from fermented soybean paste, like
8-hydroxydaidzein 37 and 30 -hydroxydaidzein 38, exhibited a
reduction of melanin synthesis in B16 melanoma cells in compar-
ison to treatment with kojic acid [123]. According to Moon and
Kim [124], hesperidin 39 showed anti-inflammatory activity,
because of decreased formation of proinflammatory cytokines, IL-
8 and TNFa, which were induced by hydrogen peroxide in human
keratinocytes (HaCaT cells). The antiulcerogenic activity of api-
genin 12, naringenin 33 and aromadendrin 40, isolated from
Euphorbia cuneata, was demonstrated in the gastric ulcer ethanol
model [125].
3. Biological properties of Ru(II)/(III) complexes with flavonoids
With the rise of Ru complexes as potentially being complemen-
tary to Pt-based anticancer chemotherapy, many Ru(II) and Ru(III)
coordination compounds and Ru(II)-based organometallics have
been reported with their anticancer activity assayed both in vitro
and in vivo. Common derivatives are often designed around the
clinically investigated Ru(III) compounds KP1019, KP1339 (IT-
139/BOLD-100), and NAMI-A and the widely studied organoruthe-
nium compound classes of RAED and RAPTA (Fig. 5) [30,126–128].
Research in this area has shown over the last decade that subtle
changes in the structure often have a significant effect on the phar-
macological properties of metal complexes. To investigate the syn-
ergistic activity between flavonoids and bioactive Ru centers, many
complexes have been prepared and studied in biological assays.
Similar effects have been observed for other combinations of bioac-
tive ligands and their metal complexes and therefore has been
M. Małecka, A. Skoczyńska, D.M. Goodman et al. Coordination Chemistry Reviews 436 (2021) 213849

Fig. 4. Schematic view of interactions between quercetin (1) and iNOS (PDB ID: 1M9T) (left) and of 5-LOX (PDB ID 3V99) with its inhibitor velutin 24 (right).

Fig. 5. Structures of ruthenium(III) compounds investigated in clinical trials and of widely investigated Ru(II) anticancer agents.

Fig. 6. Structures of RuII(polypyridyl)(flavonoid) compounds.

7
M. Małecka, A. Skoczyńska, D.M. Goodman et al. Coordination Chemistry Reviews 436 (2021) 213849

used as a design concept towards multimodal anticancer agents
[1,30,129–132]. The mode of action of such multimodal anticancer
agents will be influenced by the stability of the complexes formed
which can be exploited to achieve a targeted anticancer effect.
While in the case of PtIV compounds, reduction of the Pt center
may induce the release of bioactive ligands [133], in other cases
the complex may remain intact and exhibit biological activity in
its synthesized form, for example, by interacting at the interface
of two biomolecular targets [132]. On the other hand, slow ligand
exchange could allow for the ligand to exert its function while the
metal fragment may coordinate to another biomolecule. Such fea-
tures can be influenced by the nature of the selected metal center
and its oxidation state and allow, in combination with the selection
of proper ancillary ligands, fine-tuning of the biological activity of
the complex.
3.1. Ruthenium compounds of O-donor flavonoids
3.1.1. Ruthenium coordination compounds – From mono- to dinuclear
anticancer agents
Ru–bipyridine complexes and their structural analogues have
been investigated for their DNA binding ability and photochemical
properties [134]. Unlike cisplatin, their DNA interactions are, how-
ever, based on intercalation rather than covalent bond formation
and therefore the compounds were expected to feature modes of
action different to cisplatin and therewith other tumor types may
be targeted.
In order to introduce flavonoids as ligands into polypyridine-Ru
complexes, precursors such as [Ru(bpy)2Cl2] (bpy = 2,20 -bipyridine)
and [Ru(phen)2X2] (phen = 1,10-phenanthroline; X2 = Cl2, CO3) are
frequently used [135,136]. For example, heteroleptic ruthenium
bis-bpy 41a-41d and bis-phen 42a-42d (Fig. 6) complexes of quer-
cetin 1, morin 21, chrysin 23, and 3-hydroxyflavone 14 were
obtained after activation of the ligands with NaOMe (Fig. 6)
[137]. These complexes featured flavonoids coordinating to the
metal center through their carbonyl groups and a neighboring
hydroxyl group after deprotonation to yield 5- or 6-membered
chelates. The intrinsic fluorescence of tryptophan in BSA was used
to investigate the binding to BSA which was suggested to occur
through hydrophobic interactions, as would be expected for com-
plexes of solely bidentate ligands. Similarly, the ethidium bromide
substitution assay suggested intercalative binding to DNA. The
cytotoxic activity was assayed in SW620 (metastatic colorectal
adenocarcinoma), HepG2 (hepatocellular carcinoma), MCF-7
(breast adenocarcinoma) and HeLa (cervical carcinoma) cells(Sup-
porting Information). Only [Ru(bpy)2(d)]+ 41d was consistently
active across the cell lines investigated and d was the most potent
ligand. Interestingly, the authors observed very inconsistent IC50
values with significant standard errors which may be a sign of sec-
ondary factors such as aqueous solubility and ligand exchange
reactions occurring during the analysis. Furthermore, some modest
antimicrobial activity was observed for gram-positive bacteria.
Mishra and Singh investigated structural analogues of 41d and
42d for their antibacterial activity [113,138]. However, the lack
of comparison with standard compounds makes it difficult to judge
the potential of the compound type for further investigations.
Introduction of hesperidin led to the preparation of cis-[Ru
(phen)2(hesperidin)](PF6) which, however, was found to be non-
cytotoxic, probably due to the high hydrophilicity of the complex
[139]. It was found to inhibit acetylcholinesterase although at rel-
atively high concentrations (IC50 63.6 lM).
Gasser et al. expanded the series of compounds to the 4,7-
diphenyl-1,10-phenanthroline (DIP) derivatives 43b, 43c, 43e,
and 43f with the corresponding ligands (Fig. 6) [140]. In cytotoxi-
city assays in a broad panel of cell lines, 43e and 43f were signifi-
cantly more active than their analogous free ligands, while 43c was
slightly more cytotoxic than its chrysin ligand c, and 43b and
morin 21 were inactive (Table 1). Comparison of the cytotoxic
activity of 43f showed that the compound was similarly potent
as the standard anticancer agents cisplatin and doxorubicin. Fur-
ther comprehensive studies on the cellular uptake revealed that
the dichlorido precursor [RuII(DIP)2Cl2] was more effectively accu-
mulating in MDA-MB-435S cells than 43f but was an order of mag-
nitude less potent in the cell line, which may be influenced by
several factors, such as the charge state of the complex, labile
ligands, and impact of the genistein 5 ligand on the mode of action.
To determine the mechanism of drug uptake (Fig. 7), MDA-MB-
435S and MCF-7 cells were incubated with 43f and for comparison
with the precursor [RuII(DIP)2Cl2] at 4 °C, which slows passive dif-
fusion and active transport as compared to studies at 37 °C, after
addition of the metabolic inhibitors 2-deoxy-D-glucose and oligo-
mycin to block the cellular metabolism by inhibiting ATP produc-
tion, of chloroquine and ammonium chloride to slow endocytic
pathways, and of tetraethylammonium chloride to interfere with
cation transporters [140]. The studies indicate a passive transport
mechanism into the cell for 43f in both cell lines, while the precur-
sor was actively transported into MDA-MB-435S cells and pas-
sively into MCF-7. The mode of action of 43f was suggested to be
related to the inhibition of mitochondrial function, glycolysis and
cytosolic ATP production. The latter feature appears to be specific
to the flavonoid complexes, as structurally related compounds only
inhibited mitochondrial activity but not glycolysis [141–143].
Srishailam et al. employed a phenanthroline linker to connect
the bioactive chromone ligand g to bipyridine or phenanthroline
ruthenium scaffolds [144]. These compounds showed moderate
antiproliferative and antibacterial activities (Supporting

Table 1
IC50 values (mM) for the free flavonoid ligands, their RuII(4,7-diphenyl-1,10-phenanthroline)(flavonoid) complexes, cisplatin and doxorubicin in the human cell lines MCF-7
(ductal carcinoma), FaDU (pharynx carcinoma), MDA-MB-435S (melanoma), U87 (glioblastoma), RPE-1 (normal retinal pigmented epithelium) HEK293 (embryonic kidney) with
48 h incubation times [140].

Compound IC50 / lM
MCF-7 FaDU MDA-MB-435S U87 RPE-1 HEK293
b >100 >100 >100 >100 >100 >100
c 62.59 ± 3.23 95.06 ± 11.55 79.37 ± 8.13 91.14 ± 13.76 >100 26.80 ± 2.79
e >100 >100 >100 >100 >100 >100
f >100 >100 >100 >100 >100 75.85 ± 0.84
cisplatin 19.69 ± 1.63 5.17 ± 0.21 17.62 ± 0.54 6.97 ± 0.46 39.9 ± 9.14 2.27 ± 0.67
doxorubicin 9.39 ± 1.37 1.55 ± 0.18 5.55 ± 1.37 0.59 ± 0.03 14.9 ± 1.31 0.21 ± 0.03
[Ru(DIP)2Cl2] >50 >50 27.73 ± 5.33 25.59 ± 0.29 3.13 ± 0.28 12.11 ± 1.30
43b >50 >50 >50 >50 >50 >50
43c >50 >50 27.73 ± 5.33 25.59 ± 0.29 23.21 ± 8.08 33.02 ± 3.25
43e >50 38.21 ± 5.22 24.48 ± 1.92 30.72 ± 1.48 19.72 ± 8.23 26.46 ± 3.20
43f 16.67 ± 3.93 5.21 ± 0.73 2.64 ± 0.43 5.21 ± 1.74 2.36 ± 0.77 0.72 ± 0.10

8
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
Fig. 7. Cellular uptake of (A) [RuII(DIP)2Cl2] and (B) 43f in MDA-MB-435S and MCF-
7 cells investigated by ICP-MS under different conditions. Reproduced with
permission from ref. [140] Ó ACS 2020.
Information). Additionally, they intercalated into ct-DNA, while
not causing photocleavage of plasmid DNA [121]. Similarly,
Gramni et al. functionalized coumarin with a 2,20 -dipicolylamine
linker to synthesize a fac-trichlorido RuIII complex which can bind
to ct-DNA but does not have significant DNA cleavage ability or
cytotoxicity [145].
During the development of RuIII anticancer agents, it became
apparent that the introduction of DMSO ligands had a beneficial
effect in terms of the biological activity. This resulted in the clinical
development of NAMI-A {imidazolium trans-[RuCl4(DMSO)(imida-
9
Coordination Chemistry Reviews 436 (2021) 213849
Fig. 8. Chemical and molecular structures of the RuII complexes 45–47 and a
dimetallic analogue 48.
zole)]} as an antimetastatic agent. In the preparation of complexes
of chalcone and flavone, Mishra et al. employed cis-[RuCl2(DMSO)4]
as a Ru precursor which was converted into 45 and the chalcone
derivative (Fig. 8) [119]. Analogous Ru(II)-kaempferol (46; Fig. 8)
showed potent antiproliferative activity against A549 cells possibly
caused by DNA damage at a concentration of 20 lM perhaps due to
ROS production [146]. Minimal cytotoxic effects were observed in
WI-38 and HDFa cells for Ru(II)-quercetin (47; Fig. 8) [147]. The di-
Ru compound 48 (Fig. 8) is structurally related to 47. The molecu-
lar structure of 48 (Fig. 8) indicates a high level of planarity for the
flavone ligand which may be beneficial to act as an intercalator.
Both derivatives 45 and 48 showed incubation time-dependent
cytotoxicity in Dalton lymphoma cells, which seemed to be largely
due to the potency of the bidentate ligand [119]. In a similar
approach, the same group expanded the series of compounds
toward dimetallic 48 with both Ru centers coordinated to one chlo-
rido and three DMSO ligands, either S- or O-bound [148], as well as
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
to bisflavone-Ru complexes and flavone complexes with varying
ancillary ligands [149]. While for the former the cytotoxicity was
not investigated, the authors suggest different DNA binding ability
of chalcone and flavone derivatives, although the suggested differ-
ence in conjugation may not be the reason for the contrasting
behavior [148]. For the bisflavone-Ru complexes, issues around
solubility in cell culture medium do not allow to draw final conclu-
sions on the antiproliferative and anti-HIV activity of the com-
pounds while the structural characterization of the complexes
would benefit from further investigations [149]. This observation
demonstrates the often poor solubility observed for Ru(flavone)
complexes which needs to be addressed to make them viable can-
didates for drug development. Roy et al. reported a diverse set of
interesting biological studies for Ru complexes of chrysin and bai-
calein including in vivo data [150,151]. However, it is doubtful that
the complexes were obtained in pure form, given that there were
either no shifts observed in the 1H NMR and IR spectra, the assign-
ments of the peaks in the mass spectra were significantly off com-
pared to the theoretical values, and/or elemental analysis data was
not included. Therefore, all the biological investigations must be
considered under this light and are most probably not meaningful.
For a related class of [bis(3-hydroxyflavone)Ru(DMSO)2] com-
plexes, the cytotoxicity of the flavonol ligands was slightly lower
than of the respective Ru complexes in the breast cancer cell line
MCF-7, with the potency of the ligand determining that of the com-
plex (Supporting Information) [152]. The effect of metal coordina-
tion was reflected in cell cycle distribution studies where it shifted
a slightly higher number of cells into the G1 phase and more cells
were apoptotic, while the G2 and S phase distributions seemingly
declined. However, it remains unclear if the changes were statisti-
cally significant. As for the Ru(chrysin)2 complexes mentioned
above [150], the characterization of the complexes is inconclusive.
In addition to bisflavonoid complexes with the ligand featuring
an O,O-bidentate chelation motif, Ru compounds with N,O-
coordinating ligands have been reported [153,154]. Ochocki and
colleagues reported the dehydrogenative alcoholysis of 3-
aminoflavone 49 in methanol or ethanol and the presence of RuCl3
to yield the [Ru(3-imino-2-alkoxyflavanone)2Cl2] complexes cis-di
chloridobis(3-imino-2-methoxyflavanone)Ru(II)3H2O 50OMe and
cis-dichloridobis(3-imino-2-ethoxyflavanone)Ru(II) 2H2O 50OEt.
Independent of the nature of the alkoxy group, the compounds
were less potent than cisplatin in bladder carcinoma EJ cells and
mouse leukemia cells L1210 but were more active in the
cisplatin-resistant variants with IC50 values in the low lM range.
Lymphocytes were used as models for healthy cells in which the
Ru compounds were an order of magnitude less cytotoxic than cis-
platin. These results suggest a different mode of action to cisplatin
Fig. 9. Molecular structure of the mixed ligand 3-hydroxyiminoflavanone/3-
nitrosoflavone RuII coordination compound 51.
10
Coordination Chemistry Reviews 436 (2021) 213849
Fig. 10. Structures of 7,30 ,40 -trihydroxyflavone 53h (top) and chrysin 53c and
tectochrysin 53cMe (bottom) complexes of the trithiacyclononane RuII dimethyl
sulfoxide scaffold.
which is not surprising given the significant structural differences.
Further biological experiments to elucidate the reason for the
higher potency in cisplatin-resistant cells revealed a lower level
of active caspase-8 in the cisplatin-resistant variant over the wild
type cells after treatment with either Ru compound although the
effect was more pronounced for the methoxy 50OMe over the
ethoxy 50OEt derivative [155]. The compounds induced DNA strand
breaks in EJ cells and to a lower extent in the resistant variant, and
it is speculated that the oxidative stress induced in both cell types
also contributed to the induction of apoptosis. In the preparation of
an analogous complex from RuCl3 and 3-hydroxyiminoflavanone,
surprisingly the mixed ligand flavanone/flavone RuII coordination
compound 51 was obtained (Fig. 9) [154]. Compound 51 was com-
pared to its analogues 50OMe and 50OEt in terms of cytotoxicity and
was found to be less potent in all cancer cell lines but also in lym-
phocytes, while the compounds were to a minor degree hemolytic
at higher concentrations. Interestingly, an in silico structure–activ-
ity evaluation was investigated in context of Lipinski’s rule of 5,
where none of the compounds violated more than one drug-
likeness rule. The difference in activity was explained by the
reduced lipophilicity of 51 as compared to compounds 50 which
possibly limits the cell membrane determination.
Braga and co-workers prepared 1,4,7-trithiacyclononane ([9]
aneS3) analogues 53 of 45 in which the three DMSO ligands were
substituted with the heterocyclic S-donor ligand and as flavonoids
chrysin c, tectochrysin cMe, and 7,30 ,40 -trihydroxyflavone h were
used [156] (Fig. 10). These structures allow studying the impact
of modification with Ru on the A and B rings. Unexpectedly, com-
plexation to the Ru([9]aneS3) fragment resulted in low aqueous
solubility for 53h which limited its evaluation for cytotoxic activ-
ity. However, the flavonoids used were in all cell lines more potent
than their Ru complexes and in case of chrysin and its Ru complex
51c by an order of magnitude (Supporting Information).
Overall a diverse range of Ru coordination compounds featuring
flavonoid ligands has been reported so far. It appears that in most
cases, if not all, the ligand is the dominating factor when it comes
to their antiproliferative activity. In some cases, metal coordination
seems to have an impact on biological processes, however, for def-
inite trends clearly more systematic studies are required.
M. Małecka, A. Skoczyńska, D.M. Goodman et al. Coordination Chemistry Reviews 436 (2021) 213849

Fig. 11. Chemical structures of [Ru(cym)(3-hydroxyflavone)Cl] complexes (54–61) with varying substitution of the flavone B ring, halido leaving groups, arenes and/or
quinolinone.

Table 2
Estimated 50% topoisomerase IIa inhibitory activity (lM) and in vitro anticancer activity (IC50 values in mM) of Ru(cym)Cl complexes 54–60 of 3-hydroxyflavones d in terato-
(CH1/PA-1), colon (SW480), non-small cell lung (A549), urothelial bladder (5637), large cell lung carcinoma (LCLC-103H) and pancreatic adenocarcinoma (DAN-G) compared to
cisplatin.

topoisomerase inhibition IC50 / mM Ref

CH1/PA-1 SW480 A549 5637 LCLC-103H DAN-G
d > 40 mM 1.9 ± 0.2 11 ± 3 25 ± 10 nd nd nd [157]
54d 20–40 mM 2.1 ± 0.2 9.6 ± 1.5 20 ± 2 11 ± 5 13 ± 6 12 ± 2 [157,158]
55d nd 2.8 ± 0.4 12 ± 1 27 ± 4 nd nd nd [164]
56d nd 1.6 ± 0.2 9.6 ± 1.5 16 ± 1 nd nd nd [164]
57d nd 3.2 ± 0.1 12 ± 3 19 ± 1 nd nd nd [164]
58d nd 5.5 ± 1.2 9.2 ± 1.9 28 ± 5 nd nd nd [164]
dp-Me > 40 mM 1.1 ± 0.1 6.3 ± 1.1 81 ± 9 nd nd nd [157]
54dp-Me 20–40 mM 1.8 ± 0.2 7.2 ± 0.5 17 ± 2 5.7 ± 3.2 5.2 ± 0.8 6.6 ± 2.5 [157,158]
dp-F > 40 mM 1.56 ± 0.04 7.0 ± 0.9 37 ± 10 nd nd nd [157]
54dp-F 20–40 mM 1.7 ± 0.4 7.9 ± 2.1 18 ± 1 33 ± 5 5.5 ± 5.2 12 ± 2 [157,158]
dp-Cl 20–40 mM 0.60 ± 0.10 3.7 ± 0.4 7.9 ± 1.2 nd nd nd [157]
54dp-Cl < 20 mM 0.86 ± 0.06 3.8 ± 0.5 9.5 ± 0.5 3.3 ± 1.1 13 ± 1 19 ± 7 [157,158]
55dp-Cl nd 0.86 ± 0.04 3.4 ± 0.4 7.9 ± 0.6 nd nd nd [164]
56dp-Cl nd 1.2 ± 0.3 4.7 ± 0.9 8.9 ± 0.8 nd nd nd [164]
57dp-Cl nd 0.88 ± 0.17 4.7 ± 0.6 7.8 ± 2.5 nd nd nd [164]
58dp-Cl nd 6.3 ± 1.1 21 ± 4 59 ± 1 nd nd nd [164]
54dm-F nd 1.5 ± 0.1 7.0 ± 1.0 15 ± 1 4.3 ± 2.5 4.3 ± 1.1 5.3 ± 1.6 [158]
54do-F nd 4.0 ± 0.8 24 ± 3 30 ± 1 nd nd nd [158]
cisplatin nd 0.14 ± 0.03 3.3 ± 0.4 1.3 ± 0.4 nd nd nd [157]
54dm-Cl nd 1.0 ± 0.1 7.0 ± 0.7 12 ± 2 30 ± 2 5.0 ± 3.5 19 ± 5 [158]
54do-Cl nd 7.9 ± 0.6 26 ± 1 51 ± 5 nd nd nd [158]
54dp-Br nd 1.2 ± 0.2 3.4 ± 0.1 8.6 ± 0.7 12 ± 1 19 ± 6 5.7 ± 1.9 [158]
54dm-Br nd 2.3 ± 0.7 7.2 ± 0.4 17 ± 3 5.9 ± 1.2 16 ± 4 20 ± 5 [158]
dm,p-OMe nd 2.1 ± 0.2 >25 >25 nd nd nd [163]
54dm,p-OMe nd 2.2 ± 0.5 8.7 ± 0.8 18 ± 2 nd nd nd [163]
dm,m-OMe nd 1.4 ± 0.2 >25 >25 nd nd nd [163]
54dm,m-OMe nd 1.5 ± 0.2 4.5 ± 0.2 9.0 ± 0.5 nd nd nd [163]
dm,p,m-OMe a nd 2.0 ± 0.2 8.6 ± 1.5 >25 nd nd nd [163]
54dm,p,m-OMe a nd 2.5 ± 0.3 9.7 ± 1.9 23 ± 5 nd nd nd [163]
do,o-F nd 18 ± 1 >25 >25 nd nd nd [163]
54do,o-F nd 5.1 ± 0.8 20 ± 4 55 ± 15 nd nd nd [163]
dp-CF3 nd 1.0 ± 0.1 2.6 ± 0.2 6.5 ± 1.5 nd nd nd [163]
54dp-CF3 nd nd a nd a nd a nd nd nd [163]
dacetamide nd 7.2 ± 0.3 >25 >25 nd nd nd [163]
54dacetamide nd 5.3 ± 0.5 18 ± 1 21 ± 1 nd nd nd [163]
59 nd 4.0 ± 0.2 14 ± 1 17 ± 2 nd nd nd [164]
60 nd 5.3 ± 0.2 12 ± 2 19 ± 1 nd nd nd [164]
cisplatin nd 0.14 ± 0.03 3.3 ± 0.4 1.3 ± 0.4 nd nd nd
nd, not determined; nd a, insufficient solubility; a
precipitation occurred over 24 h.

11
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
3.1.2. Bioorganoruthenium chemistry: Ru(g6-arene) complexes of O-
donor flavonoids
The development of RuII(g6-arene) complexes as anticancer
agents has gained a lot of traction over the last decades since
Sadler and Dyson reported their ethylenediamine and pta com-
plexes, respectively, with significantly differing biological activity
[29,126]. In an attempt to harvest synergistic activity by combining
bioactive metal centers with ligands with demonstrated biological
activity, a series of Ru(cym)Cl (cym = g6–p-cymene) complexes of
3-hydroxyflavones (Fig. 11) was synthesized aiming to target the
DNA–topoisomerase complex while maintaining the ability of the
complexes to undergo ligand exchange and coordinate to DNA
[157,158], as was reported for other Ru(cym) compounds
[126,159]. The Ru complexes were found to indeed inhibit topoiso-
merase IIa more effectively than the flavonol compounds [157],
while the cytotoxic activity was often very similar to that of the
bioactive ligand (Table 2), as observed already before for Ru coor-
dination compounds. The para-substituted compounds were the
most potent cytotoxins in a range of cell lines, in particular 54dp-
F and 54dp-Cl, the latter being also the most potent topoisomerase
IIa inhibitor of the series investigated. Furthermore, the com-
pounds were shown to form quickly adducts with 50 -guanosine
monophosphate, supporting the notion of having designed a mul-
timodal anticancer agent in which a DNA targeting metal moiety
was combined with a protein targeting ligand structure. However,
it became also apparent that aqueous stability had to be carefully
assessed as the formation of [(cym)Ru(OH)3Ru(cym)]+ complexes
was observed by 1H NMR spectroscopy and electrospray
ionization-mass spectrometry over longer incubation periods. Such
species are known to be very stable and to form thermodynamic
sinks unreactive towards nucleophiles [160,161].
Analogous structures of Os(cym) and Rh(Cp*) (Cp* = g5-
pentamethylcyclopentadienyl) have been reported for d, dp-Me,
dp-F and dp-F [162]. In general, very similar cytotoxic potency
was found as for the Ru(cym) complexes and in fact the flavonol
ligands with, in some cases, the complexes being more active.
The complexes were more reactive towards the amino acid
L-histidine than towards L-cysteine and glycine. While they did
not bind in protein reactivity studies to cytochrome c, adducts with
ubiquitin were detected, in particular for the Rh(Cp*) derivatives.
Similarly, the harder metal center RhIII preferred in DNA model
compound reactivity studies ATP as a binding partner over GTP
which gave a larger number of adducts with the softer RuII and OsII
Lewis acids.
As flavonoids were reported to inhibit cyclin-dependent kinases
(CDKs), the inhibitory potential of the Ru complexes was also
investigated but no link to cytotoxic activity could be established,
making them unlikely targets [157,158]. Only minor impact on the
cell cycle distribution of cells was found with a slight G2/M arrest
accompanied by a decrease of cells in G0/G1 phase. Exploiting the
intrinsic fluorescence of 54dp-F, it was found to accumulate in
the endoplasmic reticulum using confocal fluorescence
microscopy.
The library of Ru(cym)Cl complexes was expanded with ligands
that carried more than one substituent on the B ring of the flavonol
(Fig. 11) [163]. In some cases, limited aqueous solubility was
observed for the ligands which was significantly increased by
metal coordination, making such bioactive compounds more
accessible. In molecular structure investigations of a range of com-
pounds, it was suggested that a higher degree of planarity of the
flavonol ligand results in higher cytotoxic activity, while lipophilic-
ity and electronic effects took supporting roles. The compounds
investigated showed antiproliferative activity at slightly higher
IC50 values than the more potent derivatives 54dp-Cl and 54dp-F
(Table 2).
12
Coordination Chemistry Reviews 436 (2021) 213849
Efforts to increase the structural diversity of compounds
resulted in the preparation of analogues with bromido 55 and
iodido 56 leaving groups as well as with toluene 57 and biphenyl
58 as arenes and the quinolinone derivatives 60 and 61 (Fig. 11)
[164]. Introduction of a quinolinone or substitution of the chlorido
ligand for bromido or iodido did not significantly impact the bio-
logical activity of the complexes, again supporting the notion that
the antiproliferative activity is dictated by the flavone ligand.
When cym was replaced with a biphenyl ligand as the arene, how-
ever, the cytotoxicity dropped significantly for flavonols d and dp-Cl
(Table 2). This is surprising as often the introduction of larger, con-
jugated aromatic ligands has led to improved anticancer activity
for Ru(arene) complexes [159].
The impact of the arene ligand was evaluated in a comparative
study of cym complexes 52 and their N-acetyl-L-phenylalanine
ethyl ester (AcPheOEt) analogues 61 (Fig. 11) [165]. While com-
pounds 61 were stable in aqueous solution, they underwent
decomposition in DMSO and in presence of amino acids, whereas
they formed adducts with 9-ethylguanine as a DNA model through
chlorido ligand exchange. Furthermore, it was established that the
compounds damage DNA similarly to cisplatin although to a lesser
extent (Fig. 12). While the aqueous solubility of the complexes was
significantly higher than found for the cym derivatives, the cyto-
toxicity of the compounds was similar or even higher which is
unusual as aqueous solubility often correlates with lipophilicity
which in turn has significant impact on the cellular uptake. The
accumulation of 61dp-F in HCT116 cells was significantly higher
than of its cym analogue 54dp-F. This suggests a contribution of
the Phe-derived ligand beyond that of conventional arene ligands
used in the design of piano-stool organometallics.
Compound 54dp-Cl was loaded onto a poly(organo)phosphazene
resulting a dendritic structure with three of the metal complexes
attached to terminal amino groups by substituting the chlorido
ligands in 54dp-Cl [166]. However, the conjugates obtained with
non-flavonol Ru(cym) and Rh(Cp*) compounds showed higher
metal loading in the polymer solution and higher cellular accumu-
lation in SW480 and CT-26 colon carcinoma cell lines. Further-
more, the Ru(cym)(flavonol) derivative was not cytotoxic
(Supporting Information) while all the conjugates showed reduced
anticancer activity.
The Ru(cym) complexes 54d, 54dp-Cl, 54dp-F and the
structurally-related acetonitrile derivative 62d were investigated
for their photochemical reactivity which resulted in the solvent-
dependent formation of photoproducts upon irradiation at 300
and 419 nm (Scheme 1) [167]. For example, ESI-MS showed substi-
tution of the cym ligand with solvent molecules and release of CO.
The extent of CO release was dependent on the wavelength of irra-
diation and at 300 nm 0.7 equiv. of CO were detected by GC (0.4
equiv. at 419 nm). Notably, the quantum yields of the complexes
are very low suggesting that they are normally stable and only dis-
integrate upon irradiation at specific wavelengths. The reactions
observed were similar to those reported for the bpy complex 39d
under similar conditions [168,169]. In investigations on the anti-
cancer activity of 54d and 62d with and without irradiation it
was shown that the photoproducts were non-cytotoxic in Jurkat
and A549 cells. L-Histidine binding studies were performed for
62d suggesting that the flavone ligand is displaced by L-histidine
and this process was accompanied by the formation of a
precipitate.
In addition to investigating the anticancer properties of
organoruthenium(flavonoid) complexes, their inhibitory effects in
various platelet functions were investigated by Ravishankar et al.
[110]. Chrysin and other dietary flavonoids are known to exhibit
such functions and when combined with a metal center, both the
chrysin and thiochrysin complexes 54c and 54cS (Figs. 11 and
M. Małecka, A. Skoczyńska, D.M. Goodman et al. Coordination Chemistry Reviews 436 (2021) 213849

Fig. 12. DNA damaging ability in HCT116 cells as determined by flow cytometry after treatment with 54dp-F, 61dp-F, and cisplatin (30 mM each) for 6 h. Reproduced with
permission from ref. [165]. Ó ACS 2018.

Scheme 1. The formation of the main photoinduced reaction products from Ru(cym)(flavone) complexes in acetonitrile.

13), respectively, were shown to have enhanced inhibitory effects
in platelets under physiological conditions as compared to the
ligands, while they exerted slightly reduced effects in washed pla-
telets. This may be explained by higher stability of 54cs, as was also
seen for structurally-related, maltol-derived complexes were sub-
stitution of the carbonyl group resulted in the formation of thioma-
ltolato Ru compounds which were more potent anticancer agents
due to higher stability under aqueous conditions and in presence
of biological ligands [161,170,171]. The thiochrysin complex 54cS
reduced thrombus growth and volume to a 10–25% higher degree
than 54c (Fig. 14). These properties were suggested to be attribu-
ted to different physicochemical properties such as cell permeabil-
ity and reactivity to plasma proteins, while they retain the same
target as found for chrysin itself at low toxicity.
Yadav and Singh [172] introduced the heteroatoms S and Se
into the chrysin c scaffold by factionalizing it in 7-position with
thio and seleno ethers (63a–63d, Fig. 13) for a synergistic effect
with regard to radical scavenging and other biological properties
[173]. DNA and protein binding were demonstrated using spectro-
scopic methods, suggesting electrostatic interactions with DNA

13
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
Fig. 13. Structures of RuII(cym) seleno- and thioether chrysin complexes.
and with HSA by hydrogen bonding and van der Waals forces,
while docking was employed to elucidate preferred binding sites.
The Se derivatives were found to have higher binding constants
to DNA than their sulfur analogues. The potential of the com-
pounds as anticancer agents is difficult to assess as the results from
a sulforhodamine B cytotoxicity assay were not reported as IC50
values.
Overall, organoruthenium compounds have shown a lot of
potential for anticancer chemotherapeutics development and
incorporation of a flavonoid ligand has in some cases resulted in
synergistic biological activity. However, there are in some cases
questions around solubility and stability in biological media which
need to be addressed. The substitution of coordinating carbonyl
groups for thiocarbonyls may be a way of addressing the latter,
while the rich decoration of the flavonoid scaffold with hydroxyl
moieties leaves enough of flexibility for the synthetic chemist to
improve aqueous solubility. In general, the use of comparable
methods would clearly enhance the development prospect of the
compound type and further studies have to focus on obtaining
in vivo efficacy data to be able to confidently judge the potential
of the compound class for further development.
3.2. Ru(II)/(III) complexes of aminoflavonoids
In contrast to hydroxyflavones, aminoflavones do not occur nat-
urally. Pastuszko et al. [174] synthesized RuII(arene) complexes of
aminoflavone derivatives while Ochocki et al. investigated the
Fig. 14. Comparison of the time-dependent effects of chrysin c and the thiochrysin Ru complex 54cs (both at 100 lM concentrations) in the thrombus formation under
arterial flow conditions as recorded by fluorescence microscopy. Reproduced with permission from ref. [110]. Ó Nature 2017.
14
Coordination Chemistry Reviews 436 (2021) 213849
Fig. 15. The structures of ruthenium(II) complexes with aminoflavones.
reaction of 3-aminoflavone 49 derivatives with ruthenium(III)
compounds [153]. 7-Aminoflavone 64 and 6-aminoflavone 65
formed complexes after reaction with the [Ru(cym)Cl2]2 dimeric
precursor and their in vitro properties were studied in melanoma
cell lines (Fig. 15) [175]. Compound 65 and the ruthenium deriva-
tive 69 had moderate activity against melanoma cells like A375
(human melanoma cells with high metastatic potential), DMBC11
(Superficial Spreading Melanoma (SSM)), and DMBC12 (Nodular
Melanoma (NM)), with poor activity against leukemia K562 cells.
Pastuszko et al. [174,176] also investigated the cytotoxicity of
the Ru(arene) complexes of 6-aminoflavone 65 and
7-aminoflavone 64 with cym, benzene and hexamethylbenzene
arene derivatives and chlorido and iodido ligands as leaving groups
in 66–71. The highest cytotoxic activities were observed for ruthe-
nium(II) complexes with ligand 64 with the IC50 values being sim-
ilar for both melanoma cell lines (DMBC11 and DMBC12) with
DMBC12 cells being more sensitive than DMBC11. Recently, Mucha
and coworkers [177] investigated the cytotoxic effect of ruthenium
(II) and copper(II) complexes with aminoflavone ligands in the
human cancer cell lines WM 115 (melanoma cell line), HL-60
(promyelocytic leukemia cells), NALM-6 (peripheral blood
leukemia cells) and COLO 205 (colon adenocarcinoma) (Table 3).
M. Małecka, A. Skoczyńska, D.M. Goodman et al. Coordination Chemistry Reviews 436 (2021) 213849

Table 3
The in vitro anticancer activity (IC50 values in mM) of Ru(cym)Cl complexes 66–71 and the respective free ligands 64 and 65 in melanoma (DMBC11, DMBC12, and WM-115),
promyelocytic leukemia (HL-60), peripheral blood leukemia (NALM-6), and colon (COLO 205) cancer cell lines (DMCB11 & DMCB12 from [174,176] and HL-60 NALM-6, WM-115
& COLO 205 from [177].

Compound IC50 / lM
DMBC11 DMBC12 HL-60 NALM-6 WM-115 COLO 205
64 nd nd 54.5 ± 2.0 54.5 ± 2.2 90.6 ± 5.4 4.73 ± 4.6
65 nd nd 272.4 ± 38.2 66.5 ± 5.3 699.1 ± 53.6 316.9 ± 30.4
66 nd nd 79.0 ± 4.0 65.2 ± 1.3 412.1 ± 49.7 175.6 ± 29.0
66a 13.04 1.13 nd nd nd - nd
67 4.04 2.53 140.7 ± 11.4 75.8 ± 3.7 474.2 ± 40.8 381.5 ± 44.4
68 13.04 2.31 91.2 ± 5.3 62.8 ± 2.9 334.5 ± 40.8 353.0 ± 37.3
69 19.15 0.96 276.8 ± 37.2 67.0 ± 4.7 394.2 ± 26.2 406.4 ± 39.1
70 nd nd nd nd nd nd
71 nd nd nd nd nd nd

The Ru(II) complexes were less cytotoxic than the respective cop-
per(II) compounds (Supporting Information), with the copper(II)
species being more potent than the free ligands. In many cases,
the cytotoxicity of the Ru(II) complexes are lower than their corre-
sponding ligands against the NALM-6 cell line being the most
sensitive.
4. Conclusions
In this review, the structural and biological features of Ru(II)/
(III) complexes with flavonoid ligands were discussed. Flavonoids
are commonly found in plants and possess medicinal and phar-
maceutical properties. Their therapeutic targets have been sug-
gested as kinases, apoptotic proteins, growth factors, and
matrix metalloproteinases. Molecular docking investigations can
be helpful by predicting conformational changes of the protein
following ligand binding, thereby guiding efforts towards suc-
cessful synthesis of novel anticancer drugs. Due to the promising
biological properties of flavonoids, coordination to metal centers
such as Ru has been suggested to result in synergistic effects.
Indeed, in some cases, this design principle resulted in com-
pounds with improved antiproliferative and/or enzyme inhibi-
tory activity than observed for the flavonoids themselves.
Importantly, it is not yet possible to deduce unambiguous struc-
ture–activity relationships. In most compound classes, indepen-
dent of the structure of the metal complex, being
organometallic (pseudo)half-sandwich or octahedral coordination
compounds, derivatives have been shown to be potent cytotox-
ins in cancer cells. The coordination mode of the flavonoid ligand
to the metal center seems to have at least in some cases impact
on the biological activity, with ligand exchange reactions nega-
tively impacting on their biological properties. Hence the biolog-
ical activity of many complexes was driven by the flavonoid
ligands themselves potentially following cleavage from the metal
center. These are important implications when considering such
compounds for further investigation as chemotherapeutics, as
are other physicochemical properties such as solubility and
lipophilicity, which influence the drug-likeness of the complexes.
While there are encouraging signs for some of Ru(flavonoid)
complex types, future success in ruthenium-flavonoid drug
design obviously depends heavily on the choice of the ligands,
defining the reactivity of the compounds, stabilization of the oxi-
dation state of ruthenium and the overall lipophilicity of the
complex and therewith improving drug-like properties. More-
over, for the compound class, there is a lack of in vivo data avail-
able, which would be the next step to assess the viability of the
approach for further development. Overall, it is apparent that
metal complexes of flavonoids possess interesting biological
properties, which could be significant for their applications in
medicine and pharmacy.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
Financial support from Medical University of Lodz (grant No.
503/3-066-02/503-31-001 to E. Budzisz), University of Lodz (grant
No. B1811100000050.01 to M. Malecka) and the University of
Auckland is acknowledged.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.ccr.2021.213849.
References
[1] M. Grazul, E. Budzisz, Biological activity of metal ions complexes of
chromones, coumarins and flavones, Coord. Chem. Rev. 253 (21-22) (2009)
2588–2598, https://doi.org/10.1016/j.ccr.2009.06.015.
[2] E. Budzisz, B. Keppler, G. Giester, M. Wozniczka, A. Kufelnicki, B. Nawrot,
Synthesis, crystal structure and biological characterization of a novel
palladium(II) complex with a coumarin-derived ligand, Eur. J. Inorg. Chem.
2004 (22) (2004) 4412–4419, https://doi.org/10.1002/ejic.200400483.
[3] J.H. Choi, K.S. Ahn, J. Kim, Y.S. Hong, Enhanced induction of Bax gene
expression in H460 and H1299 cells with the combined treatment of cisplatin
and adenovirus mediated wt-p53 gene transfer, Exp. Mol. Med. 32 (1) (2000)
23–28, https://doi.org/10.1038/emm.2000.5.
[4] E. Zyner, J. Graczyk, J. Ochocki, Pt(II) and Pd(II) complexes of 3-aminoflavone:
in vitro and in vivo evaluation, Pharmazie. 54 (1999) 945–946. http://www.
ncbi.nlm.nih.gov/pubmed/10631759.
_
[5] B. Zurowska, A. Erxleben, Ł. Glinka, M. Łe˛czycka, E. Zyner, J. Ochocki,
Synthesis, spectroscopy and magnetism of novel metal complexes of 3-
aminoflavone (3-af). X-ray crystal structure of 3-af and [Cu(3-af)2(NO3)2],
Inorganica Chim. Acta. 362 (3) (2009) 739–744, https://doi.org/10.1016/j.
ica.2008.04.014.
[6] R.K. Graham, Y.u. Deng, E.J. Slow, B. Haigh, N. Bissada, G.e. Lu, J. Pearson, J.
Shehadeh, L. Bertram, Z. Murphy, S.C. Warby, C.N. Doty, S. Roy, C.L.
Wellington, B.R. Leavitt, L.A. Raymond, D.W. Nicholson, M.R. Hayden,
Cleavage at the Caspase-6 Site Is Required for Neuronal Dysfunction and
Degeneration Due to Mutant Huntingtin, Cell 125 (6) (2006) 1179–1191,
https://doi.org/10.1016/j.cell.2006.04.026.
[7] K.S. Ghosh, T.K. Maiti, A. Mandal, S. Dasgupta, Copper complexes of (-)-
epicatechin gallate and (-)-epigallocatechin gallate act as inhibitors of
Ribonuclease A, FEBS Lett. 580 (2006) 4703–4708, https://doi.org/10.1016/j.
febslet.2006.07.054.
[8] J.H. Fox, J.A. Kama, G. Lieberman, R. Chopra, K. Dorsey, V. Chopra, I. Volitakis,
R.A. Cherny, A.I. Bush, S. Hersch, K. Gwinn-Hardy, Mechanisms of copper ion
mediated Huntington’s disease progression, PLoS ONE 2 (3) (2007) e334,
https://doi.org/10.1371/journal.pone.0000334.
[9] M.A. Ebrahimzadeh, F. Pourmorad, A.R. Bekhradnia, Iron chelating activity,
phenol and flavonoid content of some medicinal plants from Iran, African J.
Biotechnol. 7 (2008) 3188–3192.
[10] C. Gardi, B. Arezzini, V. Fortino, M. Comporti, Effect of free iron on collagen
synthesis, cell proliferation and MMP-2 expression in rat hepatic stellate

15
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
cells, Biochem. Pharmacol. 64 (7) (2002) 1139–1145, https://doi.org/10.1016/
S0006-2952(02)01257-1.
[11] Y. Zhao, H. Li, Z. Gao, H. Xu, Effects of dietary baicalin supplementation on
iron overload-induced mouse liver oxidative injury, Eur. J. Pharmacol. 509 (2-
3) (2005) 195–200, https://doi.org/10.1016/j.ejphar.2004.11.060.
[12] A. Nakayama, M. Hiromura, Y. Adachi, H. Sakurai, Molecular mechanism of
antidiabetic zinc-allixin complexes: Regulations of glucose utilization and
lipid metabolism, J. Biol. Inorg. Chem. 13 (5) (2008) 675–684, https://doi.org/
10.1007/s00775-008-0352-0.
[13] L.H. Cazarolli, L. Zanatta, A.P. Jorge, E. de Sousa, H. Horst, V.M. Woehl, M.G.
Pizzolatti, B. Szpoganicz, F.R.M.B. Silva, Follow-up studies on glycosylated
flavonoids and their complexes with vanadium: Their anti-hyperglycemic
potential role in diabetes, Chem. Biol. Interact. 163 (3) (2006) 177–191,
https://doi.org/10.1016/j.cbi.2006.07.010.
[14] A.S. Clark, J.M. Fagan, W.E. Mitch, Selectivity of the insulin-like actions of
vanadate on glucose and protein metabolism in skeletal muscle, Biochem. J.
232 (1985) 273–276, https://doi.org/10.1042/bj2320273.
[15] K.C. Ong, H.-E. Khoo, Insulinomimetic effects of myricetin on lipogenesis and
glucose transport in rat adipocytes but not glucose transporter translocation,
Biochem. Pharmacol. 51 (4) (1996) 423–429, https://doi.org/10.1016/0006-
2952(95)02195-7.
[16] B. Singh, A. Kumar, A.K. Malik, Flavonoids biosynthesis in plants and its
further analysis by capillary electrophoresis, Electrophoresis 38 (6) (2017)
820–832, https://doi.org/10.1002/elps.201600334.
[17] W. Bors, W. Heller, C. Michel, The Chemistry of Flavonoids. Flavonoids in
Health and Disease, in: Rice-Evans (Ed.), Chem. Flavonoids, Marcel Dekker ,
1998: pp. 111–136. https://doi.org/10.1155/2013/162750.
[18] P. Pietta, Flavonoids in Medicinal Plants. Flavonoids in Health and Disease,
Marcel Dekker, 1998.
[19] S. Shukla, Higher plant flavonoids: biosynthesis and chemical ecology, in: M.
Berhow, S. Vaughn (Eds.), Allelochem. Interact. Dakshini, In Princip, CRC Press
New York, 1999: pp. 423–437.
[20] Y.Y. Lin, K.J. Ng, S. Yang, Characterization of flavonoids by liquid
chromatography—tandem mass spectrometry, J. Chromatogr. A. 629 (2)
(1993) 389–393, https://doi.org/10.1016/0021-9673(93)87054-P.
[21] S. Kumar, A.K. Pandey, Chemistry and biological activities of flavonoids: An
overview, Sci. World J. 2013 (2013) 1–16, https://doi.org/10.1155/2013/
162750.
[22] T.-Y. Wang, Q. Li, K.-S. Bi, Bioactive flavonoids in medicinal plants: Structure,
activity and biological fate, Asian J. Pharm. Sci. 13 (1) (2018) 12–23, https://
doi.org/10.1016/j.ajps.2017.08.004.
[23] M. Abid, F. Shamsi, A. Azam, Ruthenium Complexes: An Emerging Ground to
the Development of Metallopharmaceuticals for Cancer Therapy, Mini-
Reviews Med. Chem. 16 (2015) 772–786, https://doi.org/10.2174/
1389557515666151001142012.
[24] S. Thota, Editorial (Thematic Issue: Anticancer Ruthenium Complexes in Drug
Discovery and Medicinal Chemistry), Mini-Reviews Med. Chem. 16 (2016)
771–771. https://doi.org/10.2174/138955751610160503003405.
[25] H.M. Southam, J.A. Butler, J.A. Chapman, R.K. Poole, The Microbiology of
Ruthenium Complexes, in: Adv. Microb. Physiol., 2017: pp. 1–96. https://doi.
org/10.1016/bs.ampbs.2017.03.001.
[26] C.G. Hartinger, P.J. Dyson, Bioorganometallic chemistry—from teaching
paradigms to medicinal applications, Chem. Soc. Rev. 38 (2) (2009) 391–
401, https://doi.org/10.1039/B707077M.
[27] U. Jungwirth, C.R. Kowol, B.K. Keppler, C.G. Hartinger, W. Berger, P. Heffeter,
Anticancer activity of metal complexes: Involvement of redox processes,
Antioxidants Redox Signal. 15 (4) (2011) 1085–1127, https://doi.org/10.1089/
ars.2010.3663.
[28] P.J. Dyson, G. Sava, Metal-based antitumour drugs in the post genomic era,
Dalt. Trans. (16) (2006) 1929, https://doi.org/10.1039/b601840h.
[29] S.J. Dougan, P.J. Sadler, The design of organometallic ruthenium arene
anticancer agents, Chimia (Aarau). 61 (11) (2007) 704–715, https://doi.org/
10.2533/chimia.2007.704.
[30] R.G. Kenny, C.J. Marmion, Toward Multi-Targeted Platinum and Ruthenium
Drugs - A New Paradigm in Cancer Drug Treatment Regimens?, Chem. Rev.
119 (2) (2019) 1058–1137, https://doi.org/10.1021/acs.chemrev.8b00271.
[31] E. Alessio, Thirty Years of the Drug Candidate NAMI-A and the Myths in the
Field of Ruthenium Anticancer Compounds: A Personal Perspective, Eur. J.
Inorg. Chem. 2017 (2017) 1549–1560, https://doi.org/10.1002/
ejic.201600986.
[32] C. Kanadaswami, L.T. Lee, P.P.H. Lee, J.J. Hwang, F.C. Ke, Y.T. Huang, M.T. Lee,
The antitumor activities of flavonoids, In Vivo (Brooklyn). 19 (2005) 895–910.
https://doi.org/895-910. 0258-851X/2005.
[33] L. Gamet-Payrastre, S. Manenti, M.-P. Gratacap, J. Tulliez, H. Chap, B.
Payrastre, Flavonoids and the inhibition of PKC and PI 3-kinase, Gen.
Pharmacol. 32 (3) (1999) 279–286, https://doi.org/10.1016/S0306-3623(98)
00220-1.
[34] T.-B. Kang, N.-C. Liang, Studies on the inhibitory effects of quercetin on the
HL-60 leukemia cells, Biochem. Pharmacol. 54 (1997) 1013–1018, https://doi.
org/10.1016/S0006-2952(97)00260-8.
[35] Y. Graziani, E. Erikson, R.L. Erikson, The effect of quercetin on the
phosphorylatio activity of the Rous sarcoma virus transforming gene
product in vitro and in vivo, Eur. J. Biochem. 135 (3) (1983) 583–589,
https://doi.org/10.1111/j.1432-1033.1983.tb07692.x.
[36] P.C. Ferriola, V. Cody, E. Middleton, Protein kinase C inhibition by plant
flavonoids. Kinetic mechanisms and structure-activity relationships,
16
Coordination Chemistry Reviews 436 (2021) 213849
Biochem. Pharmacol. 38 (10) (1989) 1617–1624, https://doi.org/10.1016/
0006-2952(89)90309-2.
[37] L.-T. Lee, Y.-T. Huang, J.-J. Hwang, A.-L. Lee, F.-C. Ke, C.-J. Huang, C.
Kandaswami, P.-P. Lee, M.-T. Lee, Transinactivation of the epidermal growth
factor receptor tyrosine kinase and focal adhesion kinase phosphorylation by
dietary flavonoids: Effect on invasive potential of human carcinoma cells,
Biochem. Pharmacol. 67 (11) (2004) 2103–2114, https://doi.org/10.1016/j.
bcp.2004.02.023.
[38] A. Tawani, A. Kumar, Structural Insight into the interaction of Flavonoids with
Human Telomeric Sequence, Sci. Rep. 5 (2015) 1–13, https://doi.org/10.1038/
srep17574.
[39] M.T.L.Y.T. Huang, J.J. Hwang, P.P. Lee, F.C. Ke, J.H. Huang, C.J. Huang, C.
Kandaswami, E. Jr Middleton, Effects of luteolin and quercetin, inhibitors of
tyrosine kinase, on cell growth and metastasis-associated properties in A431
cells overexpressing epidermal growth factor receptor, J. Pharmacol. (1999)
999–1010, https://doi.org/10.1074/jbc.275.12.8806.
[40] T. Akiyama, J. Ishida, S. Nakagawa, H. Ogawara, S. Watanabe, N. Itoh, M.
Shibuya, Y. Fukami, Genistein, a specific inhibitor of tyrosine-specific protein
kinases, J. Biol. Chem. 262 (12) (1987) 5592–5595, https://doi.org/10.1016/
S0021-9258(18)45614-1.
[41] G.T. Merlino, Y.H. Xu, S. Ishii, A.J.L. Clark, K. Semba, K. Toyoshima, T.
Yamamoto, I. Pastan, Amplification and enhanced expression of the
epidermal growth factor receptor gene in A431 human carcinoma cells,
Science (80-.). 224 (1984) 415–417. https://doi.org/10.1126/science.6200934.
[42] Z.D. F. Traganos, B. Ardelt, M. Halko, S. Bruno, Effects of genistin of the growth
and cell cycle progression of normal human lumphocytes and human
leukemic MOLT-4 and HL-60 cells, 52 (1999) 6200–6208.
[43] C. Kandaswami, E. Perkins, G. Drzewiecki, D.S. Soloniuk, E. Middleton,
Differential inhibition of proliferation of human squamous cell carcinoma,
gliosarcoma and embryonic fibroblast-like lung cells in culture by plant
flavonoids, Anticancer. Drugs. 3 (5) (1992) 525–530, https://doi.org/10.1097/
00001813-199210000-00013.
[44] C. Kandaswami, E. Perkins, D.S. Soloniuk, G. Drzewiecki, E. Middleton,
Antitproliferative effects of citrus flavonoids on a human squamous cell
carcinoma in vitro, Cancer Lett. 56 (2) (1991) 147–152, https://doi.org/
10.1016/0304-3835(91)90089-Z.
[45] M. Leone, D. Zhai, S. Sareth, S. Kitada, J.C. Reed, M. Pellecchia, Cancer
prevention by tea polyphenols is linked to their direct inhibition of
antiapoptotic Bcl-2-family proteins, Cancer Res. (2003) 8118–8121.
[46] M.A. Avila, J.A. Velasco, J. Cansado, V. Notano, Quercetin Mediates the Down-
Regulation of Mutant p53 in the Human Breast Cancer Cell Line MDA-MB468,
Cancer Res. 54 (1994) 2424–2428.
[47] L.R. Chu, D.-C,. JUneja, General chemical composition of green tea and its
infusion, in: Chem. Appl. Green Tea, CRC Press New York, 1997: pp. 13–22.
https://doi.org/10.11402/cookeryscience.50.182.
[48] Sanjeev Shukla, Sanjay Gupta, Molecular Mechanisms for Apigenin-Induced
Cell-Cycle Arrest and Apoptosis of Hormone Refractory Human Prostate
Carcinoma DU145 Cells, Mol. Carcinog. 39 (2) (2004) 114, https://doi.org/
10.1002/mc.10168.
[49] Marc E. Bracke, Vincent Castronovo, Rita M.L. Van Cauwenberge, Peter
Coopman, Luc Vakaet, Pawel Strojny, Jean-Michel Foidart, Marc M. Mareel,
The anti-invasive flavonoid (+)-catechin binds to laminin and abrogates the
effect of laminin on cell morphology and adhesion, Exp. Cell Res. 173 (1)
(1987) 193–205, https://doi.org/10.1016/0014-4827(87)90345-4.
[50] Eleni Bagli, Maria Stefaniotou, Lucia Morbidelli, Marina Ziche, Konstantinos
Psillas, Carol Murphy, Theodore Fotsis, Luteolin inhibits vascular endothelial
growth factor-induced angiogenesis; inhibition of endothelial cell survival and
proliferation by targeting phosphatidylinositol 30 -kinase activity, Cancer Res.
64 (21) (2004) 7936–7946, https://doi.org/10.1158/0008-5472.CAN-03-3104.
[51] Graziano Lolli, Giorgio Cozza, Marco Mazzorana, Elena Tibaldi, Luca Cesaro,
Arianna Donella-Deana, Flavio Meggio, Andrea Venerando, Cinzia Franchin,
Stefania Sarno, Roberto Battistutta, Lorenzo A. Pinna, Inhibition of protein
kinase CK2 by flavonoids and tyrphostins. a structural insight, Biochemistry
51 (31) (2012) 6097–6107, https://doi.org/10.1021/bi300531c.
[52] Takeshi Yokoyama, Yuto Kosaka, Mineyuki Mizuguchi, Structural Insight into
the Interactions between Death-Associated Protein Kinase 1 and Natural
Flavonoids, J. Med. Chem. 58 (18) (2015) 7400–7408, https://doi.org/10.1021/
acs.jmedchem.5b00893.
[53] H.-L. Peng, W.-C. Huang, S.-C. Cheng, C.-J. Liou, Fisetin inhibits the generation
of inflammatory mediators in interleukin-1b–induced human lung epithelial
cells by suppressing the NF-jB and ERK1/2 pathways, Int.
Immunopharmacol. 60 (2018) 202–210, https://doi.org/10.1016/j.
intimp.2018.05.004.
[54] Lei Chen, Hui Teng, Zhen Jia, Maurizio Battino, Anca Miron, Zhiling Yu, Hui
Cao, Jianbo Xiao, Intracellular signaling pathways of inflammation modulated
by dietary flavonoids: The most recent evidence, Crit. Rev. Food Sci. Nutr. 58
(17) (2018) 2908–2924, https://doi.org/10.1080/10408398.2017.1345853.
[55] N. Yahfoufi, N. Alsadi, M. Jambi, C. Matar, The immunomodulatory and anti-
inflammatory role of polyphenols, Nutrients. 10 (2018) 1618, https://doi.org/
10.3390/nu10111618.
[56] Reetesh Kumar, Icaro P Caruso, Anwar Ullah, Marinonio Lopes Cornelio,
Marcelo Andres Fossey, Fatima Pereira de Souza, Raghuvir Krishnaswamy
Arni, Exploring the Binding Mechanism of Flavonoid Quercetin to
Phospholipase A2: Fluorescence Spectroscopy and Computational Approach,
Eur, J. Exp. Biol. 07 (05) (2017), https://doi.org/10.21767/2248-
921510.21767/2248-9215.100033.
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
[57] M. Novo Belchor, H. Hessel Gaeta, C. Fabri Bittencourt Rodrigues, C. Ramos da
Cruz Costa, D. de Oliveira Toyama, L. Domingues Passero, M. Dalastra
Laurenti, M. Hikari Toyama, Evaluation of Rhamnetin as an Inhibitor of the
Pharmacological Effect of Secretory Phospholipase A2, Molecules. 22 (2017)
1441. https://doi.org/10.3390/molecules22091441.
[58] Zuzana Hanáková, Jan Hošek, Zsófia Kutil, Veronika Temml, Přemysl Landa,
Tomáš Vaněk, Daniela Schuster, Stefano Dall’Acqua, Josef Cvačka, Ondřej
Polanský, Karel Šmejkal, Anti-inflammatory Activity of Natural Geranylated
Flavonoids: Cyclooxygenase and Lipoxygenase Inhibitory Properties and
Proteomic Analysis, J. Nat. Prod. 80 (4) (2017) 999–1006, https://doi.org/
10.1021/acs.jnatprod.6b01011.
[59] D.M. González Mosquera, Y. Hernández Ortega, P.L. Fernández, Y. González, D.
Doens, Y. Vander Heyden, K. Foubert, L. Pieters, Flavonoids from Boldoa
purpurascens inhibit proinflammatory cytokines (TNF-a and IL-6) and the
expression of COX-2, Phyther, Res. 32 (9) (2018) 1750–1754, https://doi.org/
10.1002/ptr.6104.
[60] Fei Gao, Dong Wei, Tao Bian, Ping Xie, Jian Zou, Huijun Mu, Bin Zhang,
Xiaoyan Zhou, Genistein attenuated allergic airway inflammation by
modulating the transcription factors T-bet, GATA-3 and STAT-6 in a murine
model of asthma, Pharmacology 89 (3-4) (2012) 229–236, https://doi.org/
10.1159/000337180.
[61] Changda Liu, David Weir, Paula Busse, Nan Yang, Zhenwen Zhou, Charles
Emala, Xiu-Min Li, The flavonoid 7,40 -dihydroxyflavone inhibits MUC5AC
gene expression, production, and secretion via regulation of NF-jB, STAT6,
and HDAC2, Phyther. Res. 29 (6) (2015) 925–932, https://doi.org/10.1002/
ptr.5334.
[62] Douglas B. Kitchen, Hélène Decornez, John R. Furr, Jürgen Bajorath, Docking
and scoring in virtual screening for drug discovery: Methods and
applications, Nat. Rev. Drug Discov. 3 (11) (2004) 935–949, https://doi.org/
10.1038/nrd1549.
[63] Q.-N. Tran, H.R. Arabnia, Emerging Trends in Computational Biology,
Bioinformatics, and Systems Biology: Algorithms and Software Tools
(2015), https://doi.org/10.1016/C2014-0-02761-X.
[64] Sérgio Filipe Sousa, Pedro Alexandrino Fernandes, Maria João Ramos, Protein-
ligand docking: Current status and future challenges, Proteins Struct. Funct.
Genet. 65 (1) (2006) 15–26, https://doi.org/10.1002/prot.21082.
[65] H. Gohlke, G. Klebe, Approaches to the description and prediction of the
binding affinity of small-molecule ligands to macromolecular receptors,
Angew. Chemie - Int. Ed. 41 (2002) 2644–2676, https://doi.org/10.1002/
1521-3773(20020802)41:15<2644::AID-ANIE2644>3.0.CO;2-O.
[66] Yu Shan, Yan Cheng, Yi Zhang, Fu-Qin Guan, Hao Sun, Xing-cong Ren, Yu
Chen, Xu Feng, Jin-Ming Yang, Triticuside a, a dietary flavonoid, inhibits
proliferation of human breast cancer cells via inducing apoptosis, Nutr.
Cancer. 65 (6) (2013) 891–899, https://doi.org/10.1080/
01635581.2013.802001.
[67] Muhammad Furqan Akhtar, Ammara Saleem, Azhar Rasul, Mirza Muhammad
Faran Ashraf Baig, May Bin-Jumah, Mohamed M. Abdel Daim, Anticancer
natural medicines: An overview of cell signaling and other targets of
anticancer phytochemicals, Eur. J. Pharmacol. 888 (2020) 173488, https://
doi.org/10.1016/j.ejphar.2020.173488.
[68] Danielle G Smith, Tapiwanashe Magwere, Susan A Burchill, Oxidative stress
and therapeutic opportunities: Focus on the Ewing’s sarcoma family of
tumors, Expert Rev. Anticancer Ther. 11 (2) (2011) 229–249, https://doi.org/
10.1586/era.10.224.
[69] Hyeryoung Jung, Soon Young Shin, Yearam Jung, Thao Anh Tran, Hye Ok Lee,
Kang-Yeoun Jung, Dongsoo Koh, Somi Kim Cho, Yoongho Lim, Quantitative
Relationships between the Cytotoxicity of Flavonoids on the Human Breast
Cancer Stem-Like Cells MCF7-SC and Their Structural Properties, Chem. Biol.
Drug Des. 86 (4) (2015) 496–508, https://doi.org/10.1111/cbdd.12512.
[70] Fei Ding, Wei Peng, Yu-Kui Peng, Biophysical exploration of protein-flavonol
recognition: Effects of molecular properties and conformational flexibility,
Phys. Chem. Chem. Phys. 18 (17) (2016) 11959–11971, https://doi.org/
10.1039/C5CP07754K.
[71] Sam-Yong Park, Takeshi Yokoyama, Naoya Shibayama, Yoshitsugu Shiro,
Jeremy R.H. Tame, 1.25 Å Resolution Crystal Structures of Human
Haemoglobin in the Oxy, Deoxy and Carbonmonoxy Forms, J. Mol. Biol. 360
(3) (2006) 690–701, https://doi.org/10.1016/j.jmb.2006.05.036.
[72] Richard Bayliss, Teresa Sardon, Isabelle Vernos, Elena Conti, Structural basis
of Aurora-A activation by TPX2 at the mitotic spindle, Mol. Cell. 12 (4) (2003)
851–862, https://doi.org/10.1016/S1097-2765(03)00392-7.
[73] Kiho Kim, Hyeonjeong Choe, Yujeong Jeong, Jun Hee Lee, Sungwoo Hong, Ru
(II)-Catalyzed Site-Selective Hydroxylation of Flavone and Chromone
Derivatives: The Importance of the 5-Hydroxyl Motif for the Inhibition of
Aurora Kinases, Org. Lett. 17 (10) (2015) 2550–2553, https://doi.org/10.1021/
acs.orglett.5b01138.
[74] R.E. Kartasasmi, R. Herowati, T. Gusdinar, Docking study of quercetin
derivatives on inducible Nitric Oxide Synthase and prediction of their
absorption and distribution properties, J. Appl. Sci. 10 (23) (2010) 3098–
3104, https://doi.org/10.3923/jas.2010.3098.3104.
[75] R.J. Rosenfeld, E.D. Garcin, K. Panda, G. Andersson, A. Åberg, A.V. Wallace, G.M.
Morris, A.J. Olson, D.J. Stuehr, J.A. Tainer, J.A. Tainer, E.D. Getzoff, Conformational
changes in nitric oxide synthases induced by chlorzoxazone and nitroindazoles:
Crystallographic and computational analyses of inhibitor potency, Biochemistry
41 (2002) 13915–13925, https://doi.org/10.1021/bi026313j.
[76] X. Chen, S. Sood, C.S. Yang, N. Li, Z. Sun, Five-lipoxygenase pathway of
arachidonic acid metabolism in carcinogenesis and cancer chemoprevention,
17
Coordination Chemistry Reviews 436 (2021) 213849
Curr. Cancer Drug Targets. 6 (2006) 613–622, https://doi.org/10.2174/
156800906778742451.
[77] J. Jawien, R. Korbut, The current view on the role of leukotrienes in
atherogenesis, J. Physiol. Pharmacol. 61 (2010) 647–650.
[78] Oliver Werz, Dieter Steinhilber, Therapeutic options for 5-lipoxygenase
inhibitors, Pharmacol. Ther. 112 (3) (2006) 701–718, https://doi.org/
10.1016/j.pharmthera.2006.05.009.
[79] W. Berger, M.T.M. De Chandt, C.B. Cairns, Zileuton: Clinical implications of 5-
Lipoxygenase inhibition in severe airway disease, Int. J. Clin. Pract. 61 (2007)
663–676, https://doi.org/10.1111/j.1742-1241.2007.01320.x.
[80] Swati Singh, Manika Awasthi, Veda P. Pandey, Upendra N. Dwivedi,
Lipoxygenase directed anti-inflammatory and anti-cancerous secondary
metabolites: ADMET-based screening, molecular docking and dynamics
simulation, J. Biomol. Struct. Dyn. 35 (3) (2017) 657–668, https://doi.org/
10.1080/07391102.2016.1159985.
[81] O. Rådmark, B. Samuelsson, Microsomal prostaglandin e synthase-1 and 5-
lipoxygenase: Potential drug targets in cancer, J. Intern. Med. 268 (2010) 5–
14, https://doi.org/10.1111/j.1365-2796.2010.02246.x.
[82] A. Zahir, A. Jossang, B. Bodo, J. Provost, J.-P. Cosson, T. Sévenet, DNA
topoisomerase I inhibitors: Cytotoxic flavones from Lethedon tannaensis, J.
Nat. Prod. 59 (1996) 701–703, https://doi.org/10.1021/np960336f.
[83] Heather L. Howie, Rachel A. Katzenellenbogen, Denise A. Galloway,
Papillomavirus E6 proteins, Virology 384 (2) (2009) 324–334, https://doi.
org/10.1016/j.virol.2008.11.017.
[84] P. Kulshrestha, V.K. Jatav, S. Sharma, Screening of effective herbal compounds
for inhibition of human papillomavirus type 16 E6 protein, Imternational Res,
J. Humanit. Eng. Pharm. Sci. 2 (2015).
[85] Naglaa Ashmawy, Mohamed Ashour, Michael Wink, Mohamed El-Shazly,
Fang-Rong Chang, Noha Swilam, Ashraf Abdel-Naim, Nahla Ayoub,
Polyphenols from Erythrina crista-galli: Structures, molecular docking and
phytoestrogenic activity, Molecules 21 (6) (2016) 726, https://doi.org/
10.3390/molecules21060726.
[86] L. Celik, J.D.D. Lund, B. Schiøtt, Conformational dynamics of the estrogen
receptor a: Molecular dynamics simulations of the influence of binding site
structure on protein dynamics, Biochemistry 46 (2007) 1743–1758, https://
doi.org/10.1021/bi061656t.
[87] Yacong Bo, Jinfeng Sun, Mengmeng Wang, Jizhe Ding, Quanjun Lu, Ling Yuan,
Dietary flavonoid intake and the risk of digestive tract cancers: A systematic
review and meta-analysis, Sci. Rep. 6 (1) (2016), https://doi.org/10.1038/
srep24836.
[88] G.-L. Chen, M.-X. Fan, J.-L. Wu, N. Li, M.-Q. Guo, Antioxidant and anti-
inflammatory properties of flavonoids from lotus plumule, Food Chem. 277
(2019) 706–712, https://doi.org/10.1016/j.foodchem.2018.11.040.
[89] Xican Li, Qian Jiang, Tingting Wang, Jingjing Liu, Dongfeng Chen, Comparison
of the antioxidant effects of quercitrin and isoquercitrin: Understanding the
role of the 600 -OH group, Molecules 21 (9) (2016) 1246, https://doi.org/
10.3390/molecules21091246.
[90] Y.-Q. Guo, G.-H. Tang, L.-L. Lou, W. Li, B. Zhang, B. Liu, S. Yin, Prenylated
flavonoids as potent phosphodiesterase-4 inhibitors from Morus alba:
Isolation, modification, and structure-activity relationship study, Eur. J.
Med. Chem. 144 (2018) 758–766, https://doi.org/10.1016/j.
ejmech.2017.12.057.
[91] B. Wahlang, C. McClain, S. Barve, L. Gobejishvili, Role of cAMP and
phosphodiesterase signaling in liver health and disease, Cell. Signal. 49
(2018) 105–115, https://doi.org/10.1016/j.cellsig.2018.06.005.
[92] J.-H. Gong, D. Shin, S.-Y. Han, J.-L. Kim, Y.-H. Kang, Kaempferol suppresses
eosionphil infiltration and airway inflammation in airway epithelial cells and
in mice with allergic asthma, J. Nutr. 142 (2012) 47–56, https://doi.org/
10.3945/jn.111.150748.
[93] Zuyi Weng, Bodi Zhang, Shahrzad Asadi, Nikolaos Sismanopoulos, Alan
Butcher, Xueyan Fu, Alexandra Katsarou-Katsari, Christina Antoniou,
Theoharis C. Theoharides, Christian Taube, Quercetin is more effective than
cromolyn in blocking human mast cell cytokine release and inhibits contact
dermatitis and photosensitivity in humans, PLoS ONE 7 (3) (2012) e33805,
https://doi.org/10.1371/journal.pone.0033805.
[94] Zuyi Weng, Arti B. Patel, Smaro Panagiotidou, Theoharis C. Theoharides, The
novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells,
J. Allergy Clin. Immunol. 135 (4) (2015) 1044–1052.e5, https://doi.org/
10.1016/j.jaci.2014.10.032.
[95] Cristian Del Bo’, Martin Roursgaard, Marisa Porrini, Steffen Loft, Peter Møller,
Patrizia Riso, Different effects of anthocyanins and phenolic acids from wild
blueberry (Vaccinium angustifolium) on monocytes adhesion to endothelial
cells in a TNF-a stimulated proinflammatory environment, Mol. Nutr. Food
Res. 60 (11) (2016) 2355–2366, https://doi.org/10.1002/mnfr.201600178.
[96] Hong-Wei Zhang, Jin-Jiao Hu, Ruo-Qiu Fu, Xin Liu, Yan-Hao Zhang, Jing Li, Lei
Liu, Yu-Nong Li, Qin Deng, Qing-Song Luo, Qin Ouyang, Ning Gao, Flavonoids
inhibit cell proliferation and induce apoptosis and autophagy through
downregulation of PI3Kc mediated PI3K/AKT/mTOR/p70S6K/ULK signaling
pathway in human breast cancer cells, Sci. Rep. 8 (1) (2018), https://doi.org/
10.1038/s41598-018-29308-7.
[97] M. Kimata, M. Shichijo, T. Miura, I. Serizawa, N. Inagaki, H. Nagai, Effects of
luteolin, quercetin and baicalein on immunoglobulin E- mediated mediator
release from human cultured mast cells, Clin. Exp. Allergy. 30 (2000) 501–
508, https://doi.org/10.1046/j.1365-2222.2000.00768.x.
[98] Alexandre P. Rogerio, Cristiana L. Dora, Edinéia L. Andrade, Juliana S. Chaves,
Luis F.C. Silva, Elenara Lemos-Senna, João B. Calixto, Anti-inflammatory effect
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
of quercetin-loaded microemulsion in the airways allergic inflammatory
model in mice, Pharmacol. Res. 61 (4) (2010) 288–297, https://doi.org/
10.1016/j.phrs.2009.10.005.
[99] Wei Duan, I. Chun Kuo, Sathiyamoorthy Selvarajan, Kaw Yan Chua, Boon Huat
Bay, W. S. Fred Wong, Antiinflammatory effects of genistein, a tyrosine kinase
inhibitor, on a guinea pig model of asthma, Am. J. Respir. Crit. Care Med. 167
(2) (2003) 185–192, https://doi.org/10.1164/rccm.200205-420OC.
[100] Caini Liu, Liang Zhu, Koichi Fukuda, Suidong Ouyang, Xing Chen, Chenhui
Wang, Cun-jin Zhang, Bradley Martin, Chunfang Gu, Luke Qin, Suguna
Rachakonda, Mark Aronica, Jun Qin, Xiaoxia Li, The flavonoid cyanidin blocks
binding of the cytokine interleukin-17A to the IL-17RA subunit to alleviate
inflammation in vivo, Sci. Signal. 10 (467) (2017) eaaf8823, https://doi.org/
10.1126/scisignal.aaf8823.
[101] D. Wilson, M. Evans, N. Guthrie, P. Sharma, J. Baisley, F. Schonlau, C. Burki, A
randomized, double-blind, placebo-controlled exploratory study to evaluate
the potential of PycnogenolÒ for improving allergic rhinitis symptoms,
Phyther. Res. 24 (2010) 1115–1119, https://doi.org/10.1002/ptr.3232.
[102] Amy Rees, Georgina Dodd, Jeremy Spencer, The Effects of Flavonoids on
Cardiovascular Health: A Review of Human Intervention Trials and
Implications for Cerebrovascular Function, Nutrients. 10 (12) (2018) 1852,
https://doi.org/10.3390/nu10121852.
[103] Arrigo F.G. Cicero, Federica Fogacci, Martina Rosticci, Angelo Parini, Marina
Giovannini, Maddalena Veronesi, Sergio D’Addato, Claudio Borghi, Correction
to: Effect of a short-term dietary supplementation with phytosterols, red
yeast rice or both on lipid pattern in moderately hypercholesterolemic
subjects: A three-arm, double-blind, randomized clinical trial (Nutrition and
Metabolism (2017) 14, Nutr. Metab. 15 (1) (2018), https://doi.org/10.1186/
s12986-018-0280-0.
[104] Nicola P. Bondonno, Catherine P. Bondonno, Lauren C. Blekkenhorst, Michael
J. Considine, Ghassan Maghzal, Roland Stocker, Richard J. Woodman, Natalie
C. Ward, Jonathan M. Hodgson, Kevin D. Croft, Flavonoid-Rich Apple
Improves Endothelial Function in Individuals at Risk for Cardiovascular
Disease: A Randomized Controlled Clinical Trial, Mol. Nutr. Food Res. 62 (3)
(2018) 1700674, https://doi.org/10.1002/mnfr.201700674.
[105] J.G. Gormaz, S. Quintremil, R. Rodrigo, Cardiovascular disease: A target for the
pharmacological effects of quercetin, Curr. Top. Med. Chem. 15 (2015) 1735–
1742, https://doi.org/10.2174/1568026615666150427124357.
[106] Chiemi Kamada, Edson L. da Silva, Mayumi Ohnishi-Kameyama, Jae-Hak
Moon, Junji Terao, Attenuation of lipid peroxidation and hyperlipidemia by
quercetin glucoside in the aorta of high cholesterol-fed rabbit, Free Radic.
Res. 39 (2) (2005) 185–194, https://doi.org/10.1080/10715760400019638.
[107] X. Lin, C.H. Lin, T. Zhao, D. Zuo, Z. Ye, L. Liu, M.T. Lin, Quercetin protects
against heat stroke-induced myocardial injury in male rats: Antioxidative
and antiinflammatory mechanisms, Chem. Biol. Interact. 265 (2017) 47–54,
https://doi.org/10.1016/j.cbi.2017.01.006.
[108] Ling Ji, Qiang Du, YunTao Li, Wenzhi Hu, Puerarin inhibits the inflammatory
response in atherosclerosis via modulation of the NF-jB pathway in a rabbit
model, Pharmacol. Reports. 68 (5) (2016) 1054–1059, https://doi.org/
10.1016/j.pharep.2016.06.007.
[109] Y. Zhang, P. Liao, M. Zhu, W. Li, D. Hu, S. Guan, L. Chen, Baicalin Attenuates
Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-
Overload Mice Model, Cell. Physiol. Biochem. 41 (2017) 849–864, https://doi.
org/10.1159/000459708.
[110] Divyashree Ravishankar, Maryam Salamah, Alda Attina, Radhika Pothi,
Thomas M. Vallance, Muhammad Javed, Harry F. Williams, Eman M.S.
Alzahrani, Elena Kabova, Rajendran Vaiyapuri, Kenneth Shankland, Jonathan
Gibbins, Katja Strohfeldt, Francesca Greco, Helen M.I. Osborn, Sakthivel
Vaiyapuri, Ruthenium-conjugated chrysin analogues modulate platelet
activity, thrombus formation and haemostasis with enhanced efficacy, Sci.
Rep. 7 (1) (2017), https://doi.org/10.1038/s41598-017-05936-3.
[111] T.P. Tim Cushnie, Andrew J. Lamb, Antimicrobial activity of flavonoids, Int. J.
Antimicrob. Agents. 26 (5) (2005) 343–356, https://doi.org/10.1016/j.
ijantimicag.2005.09.002.
[112] M.M. Cowan, Plant products as antimicrobial agents, Clin. Microbiol. Rev. 12
(4) (1999) 564–582, https://doi.org/10.1128/CMR.12.4.564.
[113] Ajay K Mishra, Amita Mishra, HK Kehri, Bechan Sharma, Abhay K Pandey,
Inhibitory activity of Indian spice plant Cinnamomum zeylanicum extracts
against Alternaria solani and Curvularia lunata, the pathogenic dematiaceous
moulds, Ann. Clin. Microbiol. Antimicrob. 8 (1) (2009) 9, https://doi.org/
10.1186/1476-0711-8-9.
[114] K.A. Ohemeng, C.F. Schwender, K.P. Fu, J.F. Barrett, DNA gyrase inhibitory and
antibacterial activity of some flavones(1), Bioorganic Med. Chem. Lett. 3 (2)
(1993) 225–230, https://doi.org/10.1016/S0960-894X(01)80881-7.
[115] K. Osawa, H. Yasuda, T. Maruyama, H. Morita, K. Takeya, H. Itokawa,
Isoflavanones from the Heartwood of Swartzia polyphylla and Their
Antibacterial Activity against Cariogenic Bacteria., Chem. Pharm. Bull.
(Tokyo). 40 (1992). https://doi.org/10.1248/cpb.40.2970.
[116] Hiroyuki Haraguchi, Katsuhito Tanimoto, Yukiyoshi Tamura, Kenji Mizutani,
Takeshi Kinoshita, Mode of antibacterial action of retrochalcones from
Glycyrrhiza inflata, Phytochemistry 48 (1) (1998) 125–129, https://doi.org/
10.1016/S0031-9422(97)01105-9.
[117] Maurya, Surface Functionalization of TiO2 with Plant Extracts and their
Combined Antimicrobial Activities Against E. faecalis and E, Coli, J. Res.
Updat. Polym. Sci. (2012), https://doi.org/10.6000/1929-
5995.2012.01.01.6.
18
Coordination Chemistry Reviews 436 (2021) 213849
[118] A.K. Mishra, B.K. Singh, A.K. Pandey, In vitro-antibacterial activity and
phytochemical profiles of Cinnamomum tamala (Tejpat) leaf extracts and oil,
Rev. Infect. 1 (2010) 134–139.
[119] Rishikesh Prajapati, Santosh Kumar Dubey, Ruchi Gaur, Raj Kumar Koiri,
Brajesh Kumar Maurya, Surendra Kumar Trigun, Lallan Mishra, Structural
characterization and cytotoxicity studies of ruthenium(II)–dmso–chloro
complexes of chalcone and flavone derivatives, Polyhedron 29 (3) (2010)
1055–1061, https://doi.org/10.1016/j.poly.2009.11.012.
[120] Tarique Hussain, Bie Tan, Ghulam Murtaza, Gang Liu, Najma Rahu,
Muhammad Saleem Kalhoro, Dildar Hussain Kalhoro, Tolulope O
Adebowale, Muhammad Usman Mazhar, Zia ur Rehman, Yordan Martínez,
Shahzad Akber Khan, Yulong Yin, Flavonoids and type 2 diabetes: Evidence of
efficacy in clinical and animal studies and delivery strategies to enhance their
therapeutic efficacy, Pharmacol. Res. 152 (2020) 104629, https://doi.org/
10.1016/j.phrs.2020.104629.
[121] Ahmad Abdullah, Palaniyandi Ravanan, Kaempferol mitigates Endoplasmic
Reticulum Stress Induced Cell Death by targeting caspase 3/7, Sci. Rep. 8 (1)
(2018), https://doi.org/10.1038/s41598-018-20499-7.
[122] Yanqing Wu, Fang Wang, E. Albert Reece, Peixin Yang, Curcumin ameliorates
high glucose-induced neural tube defects by suppressing cellular stress and
apoptosis, Am. J. Obstet. Gynecol. 212 (6) (2015) 802.e1–802.e8, https://doi.
org/10.1016/j.ajog.2015.01.017.
[123] M.-J. Goh, J.-S. Park, J.-H. Bae, D.-H. Kim, H.-K. Kim, Y.-J. Na, Effects of ortho-
dihydroxyisoflavone derivatives from korean fermented soybean paste on
melanogenesis in b16 melanom cells and human skin equivalents, Phyther.
Res. 26 (2012) 1107–1112, https://doi.org/10.1002/ptr.3682.
[124] Phil-Dong Moon, Hyung-Mim Kim, Antiinflammatory effects of traditional
Korean medicine, JinPi-tang and its active ingredient, hesperidin in HaCaT
cells, Phyther. Res. 26 (5) (2012) 657–662, https://doi.org/10.1002/ptr.3627.
[125] Amani S. Awaad, Reham M. El-Meligy, Gamal A. Soliman, Natural products in
treatment of ulcerative colitis and peptic ulcer, J. Saudi Chem. Soc. 17 (1)
(2013) 101–124, https://doi.org/10.1016/j.jscs.2012.03.002.
[126] B.S. Murray, M.V. Babak, C.G. Hartinger, P.J. Dyson, The development of
RAPTA compounds for the treatment of tumors, Coord. Chem. Rev. 306 (2016)
86–114, https://doi.org/10.1016/j.ccr.2015.06.014.
[127] Samuel M. Meier-Menches, Christopher Gerner, Walter Berger, Christian G.
Hartinger, Bernhard K. Keppler, Structure-activity relationships for
ruthenium and osmium anticancer agents-towards clinical development,
Chem. Soc. Rev. 47 (3) (2018) 909–928, https://doi.org/10.1039/C7CS00332C.
[128] Sundarraman Balaji, Mohamed Kasim Mohamed Subarkhan, Rengan Ramesh,
Hangxiang Wang, David Semeril, Synthesis and Structure of Arene Ru(II)
N^O-Chelating Complexes. In Vitro Cytotoxicity and Cancer Cell Death
Mechanism, Organometallics 39 (8) (2020) 1366–1375, https://doi.org/
10.1021/acs.organomet.0c00092.
[129] C. Spoerlein, K. Mahal, H. Schmidt, R. Schobert, Effects of chrysin, apigenin,
genistein and their homoleptic copper(II) complexes on the growth and
metastatic potential of cancer cells, J. Inorg. Biochem. 127 (2013) 107–115,
https://doi.org/10.1016/j.jinorgbio.2013.07.038.
[130] K.J. Burke, L.J. Stephens, M.V. Werrett, P.C. Andrews, Bismuth(III)
Flavonolates: The Impact of Structural Diversity on Antibacterial Activity,
Mammalian Cell Viability and Cellular Uptake, Chem. Eur. J. 26 (2020) 7657–
7671.
[131] Jing-Jing Zhang, Mohamed A. Abu el Maaty, Henrik Hoffmeister, Claudia
Schmidt, Julienne K. Muenzner, Rainer Schobert, Stefan Wölfl, Ingo Ott, A
Multitarget Gold(I) Complex Induces Cytotoxicity Related to Aneuploidy in
HCT-116 Colorectal Carcinoma Cells, Angew. Chemie - Int. Ed. 59 (38) (2020)
16795–16800, https://doi.org/10.1002/anie.202006212.
[132] Hana Kostrhunova, Juraj Zajac, Lenka Markova, Viktor Brabec, Jana
Kasparkova, A Multi-action Pt IV Conjugate with Oleate and Cinnamate
Ligands Targets Human Epithelial Growth Factor Receptor HER2 in
Aggressive Breast Cancer Cells, Angew. Chemie. 132 (47) (2020) 21343–
21348, https://doi.org/10.1002/ange.202009491.
[133] Qian Cao, Dan-Jie Zhou, Zheng-Yin Pan, Gang-Gang Yang, Hang Zhang, Liang-
Nian Ji, Zong-Wan Mao, CAIXplatins: Highly Potent Platinum(IV) Prodrugs
Selective Against Carbonic Anhydrase IX for the Treatment of Hypoxic
Tumors, Angew. Chemie. 132 (42) (2020) 18715–18721, https://doi.org/
10.1002/ange.202005362.
[134] Patty K.-L. Fu, Patricia M. Bradley, Dietmar van Loyen, Heinz Dürr, Stefan H.
Bossmann, Claudia Turro, DNA photocleavage by a supramolecular Ru(II)-
viologen complex, Inorg. Chem. 41 (15) (2002) 3808–3810, https://doi.org/
10.1021/ic020136t.
[135] M. Tian, J. Li, S. Zhang, L. Guo, X. He, D. Kong, H. Zhang, Z. Liu, Half-sandwich
ruthenium(ii) complexes containing N^N-chelated imino-pyridyl ligands
that are selectively toxic to cancer cells, Chem. Commun. 53 (2017) 12810–
12813, https://doi.org/10.1039/c7cc08270c.
[136] R. Li, Y. Ma, X. Hu, W. Wu, X. Wu, C. Dong, S. Shi, Y. Lin, 2+significantly inhibits
glioblastoma growth: In vitro and vivo with fewer side-effects than cisplatin,
Dalt. Trans. 49 (2020) 8864–8871, https://doi.org/10.1039/d0dt01877e.
[137] Adnan Zahirović, Emira Kahrović, Marina Cindrić, Sandra Kraljević Pavelić,
Mirsada Hukić, Anja Harej, Emir Turkušić, Heteroleptic ruthenium
bioflavonoid complexes: from synthesis to in vitro biological activity, J.
Coord. Chem. 70 (24) (2017) 4030–4053, https://doi.org/10.1080/
00958972.2017.1409893.
[138] L. Mishra, A.K. Singh, Synthesis, spectroscopic, luminescence, electrochemical
and antibacterial studies of ruthenium(II) polypyridyl complexes containing
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
3-hydroxyflavones as co-ligand, Indian J. Chem. -Section A. 40A (2001) 1288–
1294.
[139] Regina M.M. Oliveira, Juliana F. de Souza Daniel, Rose M. Carlos, Synthesis,
spectroscopic characterization and biological activity of cis-[Ru(hesperidin)
(1,100 -phenanthroline)2](PF6) complex, J. Mol. Struct. 1031 (2013) 269–274,
https://doi.org/10.1016/j.molstruc.2012.09.066.
[140] Alexandra-Cristina Munteanu, Anna Notaro, Marta Jakubaszek, Joseph
Cowell, Mickaël Tharaud, Bruno Goud, Valentina Uivarosi, Gilles Gasser,
Synthesis, Characterization, Cytotoxic Activity, and Metabolic Studies of
Ruthenium(II) Polypyridyl Complexes Containing Flavonoid Ligands, Inorg.
Chem. 59 (7) (2020) 4424–4434, https://doi.org/10.1021/acs.
inorgchem.9b03562.
[141] Anna Notaro, Marta Jakubaszek, Nils Rotthowe, Federica Maschietto, Robin
Vinck, Patrick S. Felder, Bruno Goud, Mickaël Tharaud, Ilaria Ciofini, Fethi
Bedioui, Rainer F. Winter, Gilles Gasser, Increasing the Cytotoxicity of Ru(II)
Polypyridyl Complexes by Tuning the Electronic Structure of Dioxo Ligands, J.
Am. Chem. Soc. 142 (13) (2020) 6066–6084, https://doi.org/
10.1021/jacs.9b12464.
[142] Anna Notaro, Angelo Frei, Riccardo Rubbiani, Marta Jakubaszek, Uttara Basu,
Severin Koch, Cristina Mari, Mazzarine Dotou, Olivier Blacque, Jérémie
Gouyon, Fethi Bedioui, Nils Rotthowe, Rainer F. Winter, Bruno Goud, Stefano
Ferrari, Mickaël Tharaud, Martina Řezáčová, Jana Humajová, Pavel Tomšík,
Gilles Gasser, Ruthenium(II) Complex Containing a Redox-Active
Semiquinonate Ligand as a Potential Chemotherapeutic Agent: From
Synthesis to in Vivo Studies, J. Med. Chem. 63 (10) (2020) 5568–5584,
https://doi.org/10.1021/acs.jmedchem.0c00431.
[143] Anna Notaro, Marta Jakubaszek, Severin Koch, Riccardo Rubbiani, Orsolya
Dömötör, Éva A. Enyedy, Mazzarine Dotou, Fethi Bedioui, Mickaël Tharaud,
Bruno Goud, Stefano Ferrari, Enzo Alessio, Gilles Gasser, A Maltol-Containing
Ruthenium Polypyridyl Complex as a Potential Anticancer Agent, Chem. - A
Eur. J. 26 (22) (2020) 4997–5009, https://doi.org/10.1002/chem.201904877.
[144] A. Srishailam, N.M. Gabra, Y.P. Kumar, K.L. Reddy, C.S. Devi, D. Anil Kumar, S.S.
Singh, S. Satyanarayana, Synthesis, characterization; DNA binding and
antitumor activity of ruthenium(II) polypyridyl complexes, J. Photochem.
Photobiol. B Biol. 141 (2014) 47–58, https://doi.org/10.1016/j.
jphotobiol.2014.09.003.
[145] L. Gramni, N. Vukea, A. Chakraborty, W.J. Samson, L.M.K. Dingle, B. Xulu, J.A.
de la Mare, A.L. Edkins, I.N. Booysen, Anticancer evaluation of ruthenium(III)
complexes with N-donor ligands tethered to coumarin or uracil moieties,
Inorganica Chim. Acta. 492 (2019) 98–107, https://doi.org/10.1016/j.
ica.2019.04.018.
[146] P. Thangavel, B. Viswanath, S. Kim, Synthesis and characterization of
kaempferol-based ruthenium (II) complex: A facile approach for superior
anticancer application, Mater. Sci. Eng. C. 89 (2018) 87–94, https://doi.org/
10.1016/j.msec.2018.03.020.
[147] B.A. Lakshmi, J.Y. Bae, J.H. An, S. Kim, Facile design and spectroscopic
characterization of novel bio-inspired Quercetin-conjugated tetrakis
(dimethylsulfoxide)dichlororuthenium(II) complex for enhanced anticancer
properties, Inorganica Chim. Acta. 495 (2019) 118989-undefined. https://doi.
org/10.1016/j.ica.2019.118989.
[148] R. Gaur, L. Mishra, Bi-nuclear Ru(ii) complexes of bis-chalcone and bis-
flavonol: synthesis, characterization, photo cleavage of DNA and
Topoisomerase I inhibition, RSC Adv. 3 (2013) 12210–12219, https://doi.
org/10.1039/c3ra41451e.
[149] L. Mishra, A.K. Singh, Synthesis, spectroscopic, luminescence, electrochemical
and antitumour/anti-HIV studies of some new monomeric and dimeric
ruthenium(II) complexes of 3-hydroxy-4’-benzyloxy flavone containing
nitrogen, oxygen and sulphur donors as co-ligands, Indian J. Chem. 41A
(2002) 1826–1831.
[150] Souvik Roy, Anweshan Sil, Tania Chakraborty, Potentiating apoptosis and
modulation of p53, Bcl2, and Bax by a novel chrysin ruthenium complex for
effective chemotherapeutic efficacy against breast cancer, J. Cell. Physiol. 234
(4) (2019) 4888–4909, https://doi.org/10.1002/jcp.27287.
[151] Yixuan Wang, Li Bian, Tania Chakraborty, Torsha Ghosh, Pallakhi Chanda,
Souvik Roy, Construing the Biochemical and Molecular Mechanism
Underlying the In Vivo and In Vitro Chemotherapeutic Efficacy of
Ruthenium-Baicalein Complex in Colon Cancer, Int. J. Biol. Sci. 15 (5)
(2019) 1052–1071, https://doi.org/10.7150/ijbs.31143.
[152] Ashok Kumar Singh, Gunjan Saxena, Sahabjada, M. Arshad, Synthesis,
characterization and biological evaluation of ruthenium flavanol complexes
against breast cancer, Spectrochim. Acta - Part A Mol. Biomol. Spectrosc. 180
(2017) 97–104, https://doi.org/10.1016/j.saa.2017.02.056.
[153] J. Ochocki, M. Kasprzak, L. Chȩcińska, A. Erxleben, E. Zyner, L. Szmigiero, A.
Garza-Ortiz, J. Reedijk, Synthesis, single-crystal and solution structure
analysis and in vitro cytotoxic activity of two novel complexes of
ruthenium(ii) with in situ formed flavanone-based ligands, Dalt. Trans. 39
(2010) 9711–9718, https://doi.org/10.1039/c0dt00535e.
[154] M. Kasprzak, M. Fabijańska, L. Che˛cińska, K. Studzian, M. Markowicz-
Piasecka, J. Sikora, E. Mikiciuk-Olasik, J. Ochocki, Small differences in
structure, a large difference in activity – Comparing a new Ru(II)-3-
hydroxyiminoflavanone complex with analogous Ru(II) compounds,
Inorganica Chim. Acta. 457 (2017) 69–80, https://doi.org/10.1016/j.
ica.2016.11.021.
[155] Maria M. Kasprzak, Leszek Szmigiero, Elzbieta _ Zyner, Justyn Ochocki,
Proapoptotic activity in vitro of two novel ruthenium(II) complexes with
flavanone-based ligands that overcome cisplatin resistance in human bladder
19
Coordination Chemistry Reviews 436 (2021) 213849
carcinoma cells, J. Inorg. Biochem. 105 (4) (2011) 518–524, https://doi.org/
10.1016/j.jinorgbio.2010.12.013.
[156] J. Marques, A.M.S. Silva, M.P.M. Marques, S.S. Braga, Ruthenium(II)
trithiacyclononane complexes of 7,30 ,40 -trihydroxyflavone, chrysin and
tectochrysin: Synthesis, characterisation, and cytotoxic evaluation,
Inorganica Chim. Acta. 488 (2019) 71–79, https://doi.org/10.1016/j.
ica.2019.01.003.
[157] A. Kurzwernhart, W. Kandioller, C. Bartel, S. Bächler, R. Trondl, G.
Mühlgassner, M.A. Jakupec, V.B. Arion, D. Marko, B.K. Keppler, C.G.
Hartinger, Targeting the DNA-topoisomerase complex in a double-strike
approach with a topoisomerase inhibiting moiety and covalent DNA binder,
Chem. Commun. 48 (2012) 4839–4841, https://doi.org/10.1039/c2cc31040f.
[158] Andrea Kurzwernhart, Wolfgang Kandioller, Simone Bächler, Caroline Bartel,
Sanela Martic, Magdalena Buczkowska, Gerhard Mühlgassner, Michael A.
Jakupec, Heinz-Bernhard Kraatz, Patrick J. Bednarski, Vladimir B. Arion, Doris
Marko, Bernhard K. Keppler, Christian G. Hartinger, Structure-Activity
relationships of targeted RuII(g 6- P -Cymene) anticancer complexes with
flavonol-Derived ligands, J. Med. Chem. 55 (23) (2012) 10512–10522, https://
doi.org/10.1021/jm301376a.
[159] H. Chen, J.A. Parkinson, S. Parsons, R.A. Coxall, R.O. Gould, P.J. Sadler,
Organometallic ruthenium(II) diamine anticancer complexes: Arene-
nucleobase stacking and stereospecific hydrogen-bonding in guanine
adducts, J. Am. Chem. Soc. 124 (2002) 3064–3082, https://doi.org/
10.1021/ja017482e.
[160] Anna F. A. Peacock, Michael Melchart, Robert J. Deeth, Abraha
Habtemariam, Simon Parsons, Peter J. Sadler, Osmium(II) and
Ruthenium(II) Arene Maltolato Complexes: Rapid Hydrolysis and
Nucleobase Binding, Chem. - A Eur. J. 13 (9) (2007) 2601–2613,
https://doi.org/10.1002/chem.200601152.
[161] Wolfgang Kandioller, Christian G. Hartinger, Alexey A. Nazarov, Caroline
Bartel, Matthias Skocic, Michael A. Jakupec, Vladimir B. Arion, Bernhard K.
Keppler, Maltol-derived ruthenium-cymene complexes with tumor
inhibiting properties: The impact of ligand-metal bond stability on
anticancer activity in vitro, Chem. - A Eur. J. 15 (45) (2009) 12283–12291,
https://doi.org/10.1002/chem.200901939.
[162] Andrea Kurzwernhart, Stephan Mokesch, Erik Klapproth, Mahsa S. Adib-
Ravazi, Michael A. Jakupec, Christian G. Hartinger, Wolfgang Kandioller,
Bernhard K. Keppler, Flavonoid-based organometallics with different metal
centers - Investigations of the effects on reactivity and cytotoxicity, Eur. J.
Inorg. Chem. 2016 (2) (2016) 240–246, https://doi.org/10.1002/
ejic.201501020.
[163] M. Kubanik, J.K.Y. Tu, T. Söhnel, M. Hejl, M.A. Jakupec, W. Kandioller, B.K.
Keppler, C.G. Hartinger, Expanding on the Structural Diversity of Flavone-
Derived RutheniumII(ƞ6-arene) Anticancer Agents, Metallodrugs. 1 (2016),
https://doi.org/10.1515/medr-2015-0001.
[164] Andrea Kurzwernhart, Wolfgang Kandioller, Éva A. Enyedy, Maria Novak,
Michael A. Jakupec, Bernhard K. Keppler, Christian G. Hartinger, 3-
Hydroxyflavones vs. 3-hydroxyquinolinones: Structure-activity
relationships and stability studies on RuII(arene) anticancer complexes
with biologically active ligands, Dalt. Trans. 42 (17) (2013) 6193–6202,
https://doi.org/10.1039/C2DT32206D.
[165] S. Movassaghi, E. Leung, M. Hanif, B.Y.T. Lee, H.U. Holtkamp, J.K.Y. Tu, T.
Söhnel, S.M.F. Jamieson, C.G. Hartinger, A Bioactive l -Phenylalanine-Derived
Arene in Multitargeted Organoruthenium Compounds: Impact on the
Antiproliferative Activity and Mode of Action, Inorg. Chem. 57 (2018)
8521–8529, https://doi.org/10.1021/acs.inorgchem.8b01187.
[166] Carmen M. Hackl, Beatrix Schoenhacker-Alte, Matthias H.M. Klose, Helena
Henke, Maria S. Legina, Michael A. Jakupec, Walter Berger, Bernhard K.
Keppler, Oliver Brüggemann, Ian Teasdale, Petra Heffeter, Wolfgang
Kandioller, Synthesis and: In vivo anticancer evaluation of poly(organo)
phosphazene-based metallodrug conjugates, Dalt. Trans. 46 (36) (2017)
12114–12124, https://doi.org/10.1039/C7DT01767G.
[167] Sushma L. Saraf, Trevor J. Fish, Abby D. Benninghoff, Ashley A. Buelt, Rhett C.
Smith, Lisa M. Berreau, Photochemical reactivity of RuII(g6-p-cymene)
flavonolato compounds, Organometallics 33 (22) (2014) 6341–6351,
https://doi.org/10.1021/om5006337.
[168] Xiaozhen Han, Kevin K. Klausmeyer, Patrick J. Farmer, Characterization of the
Initial Intermediate Formed during Photoinduced Oxygenation of the
Ruthenium(II) Bis(bipyridyl)flavonolate Complex, Inorg. Chem. 55 (15)
(2016) 7320–7322, https://doi.org/10.1021/acs.inorgchem.6b00852.
[169] Xiaozhen Han, Murugaeson R. Kumar, Amanda Hoogerbrugge, Kevin K.
Klausmeyer, Mukunda M. Ghimire, Lauren M. Harris, Mohammad A. Omary,
Patrick J. Farmer, Mechanistic Investigations of Photoinduced Oxygenation of
Ru(II) Bis-bipyridyl Flavonolate Complexes, Inorg. Chem. 57 (5) (2018) 2416–
2424, https://doi.org/10.1021/acs.inorgchem.7b01384.
[170] Wolfgang Kandioller, Christian G. Hartinger, Alexey A. Nazarov, Maxim L.
Kuznetsov, Roland O. John, Caroline Bartel, Michael A. Jakupec, Vladimir B.
Arion, Bernhard K. Keppler, From pyrone to thiopyrone ligands-rendering
maltol-derived ruthenium(II)-arene complexes that are anticancer active
in vitro, Organometallics 28 (15) (2009) 4249–4251, https://doi.org/10.1021/
om900483t.
[171] Wolfgang Kandioller, Andrea Kurzwernhart, Muhammad Hanif, Samuel M.
Meier, Helena Henke, Bernhard K. Keppler, Christian G. Hartinger, Pyrone
derivatives and metals: From natural products to metal-based drugs, J.
Organomet. Chem. 696 (5) (2011) 999–1010, https://doi.org/10.1016/j.
jorganchem.2010.11.010.
M. Małecka, A. Skoczyńska, D.M. Goodman et al.
[172] Shipra Yadav, Jai Deo Singh, Synthesis and preliminary biological evaluation
for the anticancer activity of organochalcogen (S/se) tethered chrysin-based
organometallic RuII(g6-p-cymene) complexes, J. Biomol. Struct. Dyn. 37 (13)
(2019) 3337–3353, https://doi.org/10.1080/07391102.2018.1513867.
[173] Erin E. Battin, Julia L. Brumaghim, Antioxidant activity of sulfur and
selenium: A review of reactive oxygen species scavenging, glutathione
peroxidase, and metal-binding antioxidant mechanisms, Cell Biochem.
Biophys. 55 (1) (2009) 1–23, https://doi.org/10.1007/s12013-009-9054-7.
[174] Adam Pastuszko, Karolina Niewinna, Malgorzata Czyz, Andrzej Jóźwiak,
Magdalena Małecka, Elzbieta Budzisz, Synthesis, X-ray structure,
electrochemical properties and cytotoxic effects of new arene ruthenium(II)
complexes, J. Organomet. Chem. 745-746 (2013) 64–70, https://doi.org/
10.1016/j.jorganchem.2013.07.020.
[175] Stefan Wirth, Andreas U. Wallek, Anna Zernickel, Florian Feil, M. Sztiller-
Sikorska, K. Lesiak-Mieczkowska, Christoph Bräuchle, Ingo-Peter Lorenz, M.
20
Coordination Chemistry Reviews 436 (2021) 213849
Czyz, Tautomerization of 2-nitroso-N-arylanilines by coordination as N, N’-
chelate ligands to rhenium(i) complexes and the anticancer activity of newly
synthesized oximine rhenium(i) complexes against human melanoma and
leukemia cells in vitro, J. Inorg. Biochem. 104 (7) (2010) 774–789, https://doi.
org/10.1016/j.jinorgbio.2010.03.014.
[176] A. Pastuszko, K. Majchrzak, M. Czyz, B. Kupcewicz, E. Budzisz, The synthesis,
lipophilicity and cytotoxic effects of new ruthenium(II) arene complexes with
chromone derivatives, J. Inorg. Biochem. 159 (2016) 133–141, https://doi.org/
10.1016/j.jinorgbio.2016.02.020.
[177] P. Mucha, P. Hikisz, K. Gwoździński, U. Krajewska, A. Leniart, E. Budzisz,
Cytotoxic effect, generation of reactive oxygen/nitrogen species and
electrochemical properties of Cu(ii) complexes in comparison to half-
sandwich complexes of Ru(ii) with aminochromone derivatives, RSC Adv. 9
(2019) 31943–31952, https://doi.org/10.1039/c9ra05971g.