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International Journal of

Molecular Sciences

Review
Transition Metal Intercalators as Anticancer
Agents—Recent Advances
Krishant M. Deo 1,2,† , Benjamin J. Pages 1,2,† , Dale L. Ang 1,2 , Christopher P. Gordon 2
and Janice R. Aldrich-Wright 1,2, *
1 Nanoscale Organisation and Dynamics Group, Western Sydney University, Campbelltown, NSW 2560,
Australia; K.Deo@westernsydney.edu.au (K.M.D.); B.Pages@westernsydney.edu.au (B.J.P.);
D.Ang@westernsydney.edu.au (D.L.A.)
2 School of Science and Health, Western Sydney University, Campbelltown, NSW 2560, Australia;
C.Gordon@westernsydney.edu.au
* Correspondence: J.Aldrich-Wright@westernsydney.edu.au; Tel.: +612-4620-3218
† These authors contributed equally to this work.

Academic Editors: Sotiris Hadjikakou and Nick Hadjiliadis
Received: 16 August 2016; Accepted: 23 October 2016; Published: 31 October 2016

Abstract: The diverse anticancer utility of cisplatin has stimulated significant interest in the
development of additional platinum-based therapies, resulting in several analogues receiving clinical
approval worldwide. However, due to structural and mechanistic similarities, the effectiveness of
platinum-based therapies is countered by severe side-effects, narrow spectrum of activity and the
development of resistance. Nonetheless, metal complexes offer unique characteristics and exceptional
versatility, with the ability to alter their pharmacology through facile modifications of geometry
and coordination number. This has prompted the search for metal-based complexes with distinctly
different structural motifs and non-covalent modes of binding with a primary aim of circumventing
current clinical limitations. This review discusses recent advances in platinum and other transition
metal-based complexes with mechanisms of action involving intercalation. This mode of DNA
binding is distinct from cisplatin and its derivatives. The metals focused on in this review include
Pt, Ru and Cu along with examples of Au, Ni, Zn and Fe complexes; these complexes are capable of
DNA intercalation and are highly biologically active.

Keywords: cancer; intercalate; transition metals; DNA; cytotoxicity; DNA binding; platinum

1. Introduction
The anticancer activity of the platinum-based complex, cisplatin (Figure 1), was discovered
in the 1960s and has since been used extensively for the treatment of various cancers including
ovarian, testicular, lung and breast cancer [1–3]. This activity, however, is moderated by dose-limiting
side-effects (nephro-, neuro- and ototoxicity) and development of resistance (acquired or intrinsic) [4].
In attempts to overcome the aforementioned, thousands of analogues have been synthesised,
however, of these, only carboplatin (Figure 1) and oxaliplatin (Figure 1) have been approved for
worldwide use. These complexes exhibit different side-effects and overcome some cisplatin resistance,
respectively, although otherwise they demonstrate no significant improvements in efficacy overall [5,6].
This may be attributed to their similar geometrical configurations as they conform to the original
structure-activity relationships that were reported requirements for exhibiting anticancer activity i.e.,
a neutral platinum(II) complex containing am(m)ine ligands and leaving group(s) that can be replaced
during aquation [7,8]. The anticancer activity of cisplatin is generally attributed to its coordinative
interaction with DNA. Upon entering the cell, the chloride ligands are substituted by water, forming
strong electrophiles that can readily interact with nucleophilic bases of nucleic acids [6]. This results in

Int. J. Mol. Sci. 2016, 17, 1818; doi:10.3390/ijms17111818 www.mdpi.com/journal/ijms

through thestabilised insertion planar of a complexaromatic π–π stackingrings where within and non-covalent twodipole-dipole adjacent base interactions causing interactions. Central DNA figure sourced from PDB file 1D86 [11]. Oxygen to bend is orange. This has the potential to circumvent utility and in anticancer selection of ligands drug design that as they exhibit will coordinate.14]. Chemical structures of cisplatin. through a series of events. The compound tetrahedral 1. formation of covalently J. planar series within two of aromatic adjacent atypical rings base where metal anticancer pairs of non-covalent DNA complex [12]. [12]. and nitrogen is blue/purple. Intercalation with A promising is thedelivery insertion or a series of targeting complex of agents.14]. resulting in elongation Figure of 2. madewith to developincluding deliverycomplexes complexes or targeting with that target different agents. The as ethidium octahedralThe tetrahedral bromide complex [Cu(phen) while[Ru(phen) [Ru(bpy) 2 ]is (where 3]2+ 2(dppz)] 2+ to intercalate and unwind DNA as effectively as ethidium bromide while [Ru(bpy)2(dppz)]2+ . complexes oranticancer that target atypical complexes cellular that interact complexwith components metal other are thanDNADNA. The octahedral complex [Ru(phen)3]2+ is able chain) I in bound Escherichia with coli. Schematic representation of a metal complex interacting with DNA. non-covalent complexes combined methods. Central DNA to binding figure to DNA. change to DNA which. 17. with DNA DNA aretofacilitated unwind andextend and stabilised through in order π–π stacking the to accommodate andmetaldipole-dipole complex pairs of DNA [12]. Mol. [Pt(terpy)(2-ME)] + (where 2-ME = been in developmentwas 2-mercaptoethanol) for decades. geometries. efficacy DNA relative through complexes to combined cisplatin non-covalent with A derivatives. 2016. 1818 2 of 16 theInt.Chemical Figure Chemical structures structures of of cisplatin.[9] with metal resulting complex of in elongation of the double-helix (left. while a Transition subsequent metal intercalators compound have6Hbeen [Pt(enC 12AO)Clin development 2] + (where for 6decades. sourced from Protein Data Bank (PDB) file 2MG8 [9] with metal complex(right. sequences while (Figure a3)subsequent [15. oxaliplatin.10-phenanthroline) was tethered reported to be toa acridine potent orange inhibitor via of an alkyl polymerase achieved through DNA cleavage (Figure 3) [17]. Schematic(left. Figure1. 2016.through Intercalators Intercalation generally incorporate non-covalent is the insertion methods. electronA promising of a complex deficient. causing the double helix to bend inserted inserted sourced frommanually) and PDB 1AIO) cisplatin covalently [10]. carbon blue/purple is cream/white rectangular panels. Sci. Intercalators generally incorporate electron deficient. also from PDB 1AIO) [10].10-phenanthroline) was reported to be a potent inhibitor of polymerase I in Escherichia coli. sourced causing from the double helix to bend (right. and nitrogen is blue/purple. J. (Figurecross-links) ultimately2) leads that induce [6]. [11]. DNA are incorporate facilitated electron Intercalation and is deficient. anditsstabilities.Int. Oxygen is orange. metal complex between the base pairs (Figure 2) [13. cisplatin. than DNA. carbon is cream/white rectangular panels. through a ultimately (mainly leads to of series 1. Transition in order to accommodate the mechanisms utility in that anticancer lead to drug the resistance design as seen they with exhibit cisplatin widely and diverse its analogues.enhanced which sequence-specificity + able wasintercalate to andfor achieved through certain DNA DNA unwind DNA cleavage sequences as (Figure (Figure effectively3) [17]. and (where selection of ligands 2-ME = 2-mercaptoethanol) that will coordinate. Mol. (right. With the aim of developing metal-based complexes that exhibit improved pharmacological With the properties.16]. 17.base Oxygen pairsisare orange. Transition metal intercalators have been in development for decades. Central DNA figure is cream/white andsourced from nitrogen PDB file 1D86The is blue/purple. inserted manually) and cisplatin covalently binding to DNA. This has the potential to circumvent recognitionmetalsofdeliver repair and dipole-dipole lead the resistance interactions. planar aromatic rings interactions. atypicaltwo within anticancer or adjacent metal complexes basethat complex interact pairs of DNA are with DNA metallointercalators. 1818 2 of 17 Int. relative efforts to complexes cisplatin have been combined derivatives. 3) [15. sourced from Protein Data Bank (PDB) file 2MG8 [9] with metal complex the double-helix (left. methods. the original platinum complex Transition metals deliver Transition metal intercalators utility in have anticancer drug design as they exhibit widely diverse geometries. enC H 12AO isthe ethylenediamine tethered to acridine orange +via an alkyl chain) bound with enhanced sequence- original platinum complex ethylenediamine tethered [Pt(terpy)(2-ME)] (where 2-ME = 2-mercaptoethanol) was shown to specificity for certain DNA to acridine (Figure sequences orange 3) via an alkyl [15. shown to thebindoriginal platinum strongly to DNAcomplex via coordination [Pt(terpy)(2-ME)]numbers. the2. to apoptosis a conformational (Figure 2) [6]. all with resistance subtly seen with different redox potentials andand analogues. and Thisextend has the in order potential to toaccommodate circumvent the metal recognition complex of repair where non-covalent interactions with DNA are facilitated and stabilised through π–π stacking between the that mechanisms base pairs to (Figure 2) [13. 2016. With the efforts aim have of been developing made to develop metal-based complexes complexes with that different efficacy relative to cisplatin derivatives. aimhave efforts of developing been made metal-based complexeswith to develop complexes thatdifferent exhibit modes improved pharmacological of action and higher properties. Sci. phosphorous represented asisblue/purple yellow. sourced sourced from is phosphorous PDB 1AIO)carbon yellow.14]. recognition and selectionof repair of mechanisms ligands that will that lead to coordinate. while a subsequent compound [Pt(enC 12AO)Cl2]+ (where 12AO is potentials and stabilities. Intercalators areinteractions with generally metallointercalators. phen [Pt(enC [Cu(phen) 6 H 2]+AO)Cl 12 (where 2 ]+which (where= enCwas H 6 12 AO is ethylenediamine 1. ultimately leads to apoptosis (Figure 2) [6]. Figure 1. carboplatin and oxaliplatin. cellular modes ofthat or complexes components action andother interact higher with than DNA.16]. resulting in elongation Figure Schematic representation a metal complex interacting DNA. Figure 2. including complexes that target cellular components exhibit modes improved of action and higher pharmacological other efficacy properties.2-intrastrand apoptosis events. delivery including promisingor targeting series of agents. all thewidely with diverse subtly different geometries. manually) and cisplatin covalently binding DNA. causing thePDB file 1D86 double helix[11]. J. stabilities. The base pairs are also phosphorous representedisasyellow. was6H shown all to bindwith subtly strongly different redox enCto6HDNA via + intercalation. Transition coordination metals deliver numbers. The base pairs are also represented as blue/purple rectangular panels.16]. 1818 bound monofunctional and bifunctional adducts (mainly 1. 17. causing seenDNA withto cisplatin unwindand and itsextend analogues. between the causing base pairs DNA (Figure to unwind 2) [13.carboplatin carboplatinand andoxaliplatin.2-intrastrand cross-links) that induce a conformational change to DNA which.2-intrastrand 2 of 16 cross-links) that induce a conformational change to DNA which. (mainly 1. intercalation. Sci. through metallointercalators. coordination redoxcisplatin potentials numbers. [10].1.double-helix representation sourced of of a metal from complex Protein interacting Data Bank with2MG8 (PDB) with file DNA. Thechain) bound[Cu(phen) tetrahedral with enhanced sequence- 2]+ (where phen = bind strongly specificity to for DNA certain via DNA intercalation. Mol. through a series of events.

3’-c]phenazine) dipyrido[3. Mol. = diamino-4. The rhodium complex. 1818 3 ]16 3 of is able to intercalate and unwind DNA as effectively as ethidium bromide while [Ru(bpy)2 (dppz)]2+ (where bpy bpy == 2. are confirmed to intercalate with DNA. J.10-phenanthrenequinone diamine). A prominent series of complexes are composed of a general scaffold of [Pt(HL)(AL)]2+. + + N N N N Pt N Cu N S N OH [Pt(terpy)2-ME]+ [Cu(phen)2]+ + 2+ N N N Cl Cl N Pt N Ru HN N N N N N [Ru(phen)3]2+ [Pt(enC6H12AO)Cl2]+ 3+ H2N 2+ HN NH N N Rh N N NH NH Ru N N N NH2 N [Rh((R. DNA.R)-Me Δ-α-[Rh((R. transition metal intercalators. intercalates specifically intercalates specificallyto thethe to major major groove grooveofofthe four the fourbase basepair pairsequence 50 -TGCA-30and sequence5′-TGCA-3′ andcancanalso alsobe bephotoactivated photoactivated resulting resulting in photoinduced oxidation of DNA (Figure (Figure 3) 3) [20].7-diazadecane and phi 2R. however the zinc complex of the same porphyrin could only bind through surface interactions due to the presence of an extra axial aqua ligand [24]. ∆-α-[Rh((R. 17. and also exhibit high cytotoxcicty toward cancerous cells.7-diazadecane and= phi 9. we focus on complexes that have had recent developments within the past three years. Sci.10-phenanthrenequinone = 9. In particular. recent advances in anticancer intercalating complexes of a variety of transition metals. 2. 1818 3 of 17 phen = 1. to intercalate with DNA. withwiththethe potential for use potential for asuse a luminescent DNA probe as a luminescent DNA (Figure(Figure probe 3) [18.3’-c]phenazine) demonstrated enhanced luminescence upon uponintercalation intercalationwith withDNA.R)-Me2trien)phi]3+ [Ru(bpy)2(dppz)]2+ Figure Figure 3. for example. the impact of transition metals on the binding properties of the Due to their intrinsic properties. This review covers through surface interactions due to the presence of an extra axial aqua ligand [24]. Platinum To date. achieved through DNA cleavage (Figure 3) [17]. The rhodium 3) [18.10-phenanthroline) was reported to be a potent inhibitor of polymerase I in Escherichia coli. This review covers recent advances in anticancer intercalating complexes of a variety of transition metals. 3. where .9R. 2016. a nickel complex of porphyrin was found intercalating ligand can be staggering [21–23]. are confirmed we focus on complexes that have had recent developments within the past three years. 17. J. which was 2+ Int.19]. Due to their intrinsic properties.2-a:2’.2’-bipyridine andand dppz dppz == dipyrido[3. and also exhibit high cytotoxcicty toward cancerous cells.2’-bipyridine 2.19]. complex. the majority of platinum anticancer research has focused on the design of cisplatin analogues that covalently bind DNA.2-a:2’. the impact of transition metals on the binding properties of the intercalating ligand can be staggering [21–23]. The octahedral complex [Ru(phen) 2016. for example. diamine). a nickel complex of porphyrin was found to bind to DNA by intercalation. In contrast intercalators have received less attention.R)-Me 2trien)phi] 3+ 2 trien)phi] 3+ (where (where Me2trienMe=2 trien 2R. [20]. however the zinc complex of the same porphyrin could only bind to bind to DNA by intercalation. there are several recent examples of platinum intercalators that exhibit exceptionally high anticancer activity. Chemical Chemical structures structures of of early early transition metal intercalators. In particular.Int. however. Mol.9R-diamino-4. Sci.

a comparative transcriptomics approach was undertaken between Pt2 and cisplatin to cytotoxicity. phen (i. 1818 4 of 17 2.R-dach) as the AL (Figure 4).3-dimethyl-dpq (dpq). The stark differences observed between Pt2 and cisplatin in altering molecular pathways may partially account for their differences in cytotoxicity.29]. Counter ions have been omitted for clarity. Int.R-dach (i. the majority of platinum anticancer research has focused on the design of cisplatin analogues that covalently bind DNA. Pt5). Pt1’ and Pt3’). Platinum To date.29].2-diaminocyclohexane (S.3’-h]quinoxaline (dpq).6-dimethyl-phen phen (56Me2phen). pathways. phen. To rationalise such a large difference in greater activity than cisplatin in various cell lines (Table 1).3-dimethyl-dpq (23Me2dpq).4’-dimethyl-bpy (44Me 2bpy) (44Me as the H 2 bpy) L andas the H either and the L either S. exhibiting the same DNA affinity [25]. Additionally.e. 2016. phen (i.R S.26]. with stark contrasts in the up.R isomer of 1. which is thought to mediate resistance resistance as it can deactivate PCs [29. Pt1’ and Pt3’).and down-regulation of numerous molecular pathways. Figure 4..3’-h]quinoxaline dipyrido[3.4’-dimethyl-bpy 4. (i. this would subsequently result in increased production of thiol thiol containing biomolecules such as thioredoxins and glutathione.S-dach (i. Sci. Figure 4. J. there areSci. indicating DNA binding influences influences the apoptotic activity of these PCs. which spectroscopic techniques as well as mass spectrometry and isothermal titration calorimetry. phen. A prominent series of complexes are composed of a general scaffold of [Pt(HL )(AL )]2+ . despite despite exhibiting the same DNA affinity [25].e.30]. Distinct differences were observed between treatment with Pt2 and cisplatin at a (yeast) [28. 17. Distinct differences were observed between treatment with Pt2 and cisplatin at a molecular level. DNA affinity is not the only factor governing the the activity of these complexes as the choice of AL has a large effect. genes regulating iron and copper transport as it can deactivate PCs [29. dpq. ** indicates indicates aa stereocentre stereocentre of of the the A L.L as the A (Figure 4). complexes of S. For complexes consisting of bpy (i. Mol. 5. Pt1) or their derivatives thereof. DNA affinity is not the only factor governing the apoptotic activity of these PCs.S. Interactions of these platinum complexes (PCs) with DNA have been studied using various Interactions of these platinum complexes (PCs) with DNA have been studied using various spectroscopic techniques as well as mass spectrometry and isothermal titration calorimetry.. bpy or 4.26]. with stark contrasts in the up.e. several recent 2016.e.2-f :2’. dpq. this would subsequently result in increased production of up-regulation of this pathway. either S or R.Int. 17. In vitro cytotoxicity assays showed greater activity than cisplatin and its analogues against a range of cell lines with a number of complexes demonstrating low-nanomolar activity against a range of cell lines with a number of complexes demonstrating low-nanomolar activity (Table 1) [27].. In contrast intercalators have received less attention.and down-regulation of numerous molecular molecular level. which provided evidence for a GC-selective intercalative binding mode and DNA affinity in the range of provided evidence for a GC-selective intercalative binding mode and DNA affinity in the range of ~1044–1066 M−1 [27].2-diaminocyclohexane (S. complexes These include complexes include dipyrido[3.. either S or R. where HL is a heterocyclic HL is a heterocyclic intercalating intercalating ligand and Aligand and AL ancillary L is a bidentate is a bidentate ligand ancillary ligand [25. which is thought to mediate containing biomolecules such as thioredoxins and glutathione. General General structures structures of of phen.or R.S or theisomer R. In vitro cytotoxicity assays showed greater activity than cisplatin and its analogues ~10 –10 M−1 [27]. Counter ions have been omitted for clarity.S or R. (23Me 2 dpq). However. 2. (Table 1) [27].e. phen. or R. a correlation was apparent between DNA binding affinity and cytotoxicity where a higher DNA a correlation was apparent between DNA binding affinity and cytotoxicity where a higher DNA binding affinity was directly proportional to increased cytotoxicity. 2. indicating DNA binding binding affinity was directly proportional to increased cytotoxicity. intercalators.R-dach) of 1. For example..6-dimethyl- 5. To rationalise such a large difference in cytotoxicity. complexes of activity of these complexes as the choice of AL has a large effect.e. . For example. a comparative transcriptomics approach was undertaken between Pt2 and cisplatin to distinguish the regulation of molecular pathways using the model organism Saccharomyces cerevisiae distinguish the regulation of molecular pathways using the model organism Saccharomyces cerevisiae (yeast) [28. Additionally.R-dach (i. Mol.(56Me bpy or 2 phen).2-f:2’. However. genes regulating iron and copper transport across the across the cell membrane were significantly up-regulated by Pt2 compared to cisplatin.e. Pt1 and Pt3) displayed higher cytotoxicity than those of R. J.S. bpy bpy platinum platinum intercalators. Pt1 and Pt3) displayed higher cytotoxicity than those of R.. Pt5). These [25.. however. AL . Pt1) or their derivatives thereof. The most promising analogue from this group of complexes is Pt2 which exhibits over 160-fold The most promising analogue from this group of complexes is Pt2 which exhibits over 160-fold greater activity than cisplatin in various cell lines (Table 1).e.S-dach S. For complexes consisting of bpy (i. 1818 examples of platinum intercalators that exhibit exceptionally high anticancer 4 of 16 activity.30].. The sulphur-assimilation pathway was shown to be suppressed by Pt2 while cisplatin The sulphur-assimilation pathway was shown to be suppressed by Pt2 while cisplatin caused an caused an up-regulation of this pathway.

7 ± 0.1 ± 0.009 ± 0.2 Pt50 5. while half of the cisplatin-treated mice perished by Day 20 [33]. Table 1.6 ± 0.d Pt6 0.1 ± 0.d. However.02 0. Sci.1 3.01 0.12 ± 0. Hence variations of the original complex were synthesised in which the intercalating moiety was substituted with benz[c]acridine to increase its size and hydrophobicity (Figure 5.41 ± 0. J. these adducts inhibit RNA polymerase II-mediated transcription more prominently than compared to cross-links by cisplatin [36].08 ± 0. via intravenous and intraperitoneal methods.06 2. this activity has not yet translated into in vivo studies.0 Oxaliplatin n. Pt8) [34].2 ± 0. Furthermore. Pt8 was reported to be .7 ± 0.36 ± 0.4 Pt40 6±2 3±1 2.5 ± 0. The stark differences observed between Pt2 and cisplatin in altering molecular pathways may partially account for their differences in cytotoxicity.Int.0 ± 0.6 ± 0.1 1.03 Pt1’ 1.5 ± 0.3 ± 0. Despite these platinum-acridine complexes exhibiting excellent in vitro cytotoxicity. with the possibility of hepatotoxicity or nephrotoxicity as a result [37]. IC50 (µM) Complex L1210 Du145 A2780 Pt1 0.03 5. Although tumour growth was slowed.1 Pt30 0.8 ± 0. this treatment did not elicit a tumour suppression response [32]. Another promising class of platinum anticancer agents are composed of variations of N-[2-(acridin-9-ylamino)ethyl]-N-methylacetimidamide. at pharmacological doses.3 Pt6’ 1. 2016. Mice treated with either Pt1 or cisplatin demonstrated a comparable decrease in mean tumour weight in relation to the control group. Values taken from reference [27].2 2.6 ± 0. BD-IX rats with peritoneal carcinomatosis (induced by intraperitoneal rat PROb colon cell inoculation) were treated with Pt2.1 Carboplatin n.07 Pt2 0.4 0. = not determined.0 ± 0. which are more disruptive than those formed by cisplatin. These complexes have demonstrated exceptional cytotoxicity with Pt7 exhibiting IC50 values down to nanomolar concentrations in non-small cell lung cancer (NSCLC) cell lines (Table 2) [34].004 Pt2’ 0.0 ± 0. In vitro cytotoxicity of Pt1–6 and Pt1’–6’ against L1210 (murine leukaemia) and Du145 (prostate cancer) and A2780 (human ovarian cancer) cell lines.16 ± 0.8 ± 0. linked by a chain of varying length to ligands conjugated around the platinum centre (Figure 5). 17.1 0.2 1.08 2. This activity has been attributed to the unique hybrid of DNA binding by these complexes which utilize both intercalation and nonfunctional adduct formation.46 ± 0.007 ± 0.d.002 0.01 0.05 0. in a separate study. in vivo studies have revealed severe unwanted toxicities in mice with xenografted NCI-H460 tumours.1 Pt5 0. Pt2 seemed to cause nephrotoxicity [32].4 2. the efficacy of Pt1 was compared to cisplatin in female Specific Pathogen Free Swiss nude mice bearing PC3 (human prostate carcinoma) tumour xenografts [33]. 1818 5 of 17 cell membrane were significantly up-regulated by Pt2 compared to cisplatin. no obvious signs of toxicity were observed in mice treated with Pt1.79 ± 0.5 Cisplatin 0. The acridine moiety is able to intercalate whilst the platinum metal forms a monofunctional adduct with DNA adjacent to the intercalation site [35]. Furthermore.0 1.4 2.7 ± 0.5 ± 0.9 ± 0. platinum levels were higher in healthy tissue than they were in the tumour. These lesions inhibit DNA synthesis through stalled replication forks and DNA double-strand breaks [35]. IC50 is the concentration at which cell growth is inhibited by 50% over 72 h.1 n.44 ± 0.002 0.2 ± 0. Furthermore. 15 ± 1 9±3 [a] Value obtained from references [25.31].10 ± 0. Despite Pt2 exhibiting potent cytotoxicity in vitro.03 1.2 6.d.35–1 [a] 1.5 ± 0.27 ± 0. 2.d. Mol.19 ± 0.01 0.04 1. n.1 Pt3 0. n.030 ± 0.0 Pt4 1.3 ± 0.

2016. The base pairs are also represented as blue/purple and nitrogen is blue/purple.009 IC50 values 50 values andof0.a new a new class classofofluminescent luminescentcyclometalated cyclometalated PCs PCshave havebeen beenreported reportedconsisting consisting of of 6-phenyl-2.004 0. has been attributed to its the Topoisomerase I-DNA complex. J. phosphorous is yellow. this IC50 value decreased when irradiated (420 nm.95 J·cm −2 ).13 0.38].019 µM [41]. [40].043 ±0.010 0.32 ± 0. revealed the compound selectively localised within the localised within the nucleus. Oxygen is orange.001 0. resulting resulting from its its ability to ability stabilise to stabilise the Topoisomerase I-DNA complex. Pt7’.95 J·cm−2).0052 0. to a lesser extent. 1818 6 of 17 slightly less cytotoxic than Pt7 (Table 2) although it was found to have significantly different cellular pharmacology and target binding properties.3-dimethylthiourea)](NO3 )2 bound 3) 2 to bound to DNA.12 ± 0.4 ± 0. 50 when irradiated (420 nm.02 0.52 ± 0. DNA to a lesser extent.5 2.06 – – Pt8’ 2. Counter-ions have been DNA. respectivelyrespectively [40].3-dimethylthiourea)](NO the acridine complex [PtCl(en)(1-{2-(acridin-9-ylamino)ethyl}-1. covalent binding through the platinum centres [41]. phosphorous is yellow. 2016.compounds. photocleavage of DNA irradiation. Oxygen is orange. has been attributed to its potent anticancer activity.24 0.13 Pt8 Pt8 0.06 0. Int. Sci.01 0. carbon is for clarity and en = ethylenediamine.0052±± 0. photocleavage of DNA was markedly enhanced [41]. 17. Platinated porphyrins Platinated porphyrins are anotherare another class class of of complexes complexes that that have have shown shown very very promising promising results results and and have the potential to be activated via light irradiation (Figure 6).4 ± 0. however.12 ± 0.08 12.019 µM [41]. More More recently. intercalation and.1 3.0002 Pt7’Pt7’ –– –– –– –– 0. as determined through a solution structure (PDB 1XRW) [39]. The base pairs are also represented as blue/purple rectangular panels. Sci.2 ± 0. DNA damage bydamage by Pt9.009µM andagainst 0. covalent binding through the platinum centres [41].010±±0. exhibits inPt9. Values taken from references [34.02 0. Pt10 is reported to interact with DNA via a dual binding mode involving intercalation and.08 12. General structure structure of platinum of platinum complexes complexes incorporating incorporating acridine acridine and and benz[c]acridine benz[c]acridine (left) (left) and and the acridine complex [PtCl(en)(1-{2-(acridin-9-ylamino)ethyl}-1. DNA photocleavage experiments photocleavage experiments showed no damage to DNA in the absence of light.01 0. Mol.4 ± 0.0001 0.5 2. Pt8 and Pt8’ against human NSCLC cell lines and HL-60 leukaemia Table 2. which may result in a more favourable therapeutic window in vivo. 17. Mol. The [40].Int.24±± 0. and Pt8’ against human NSCLC cell lines and HL-60 leukaemia cells. In vitro studies of Pt10 in was markedly enhanced cisplatin-resistant human [41]. General 5.01 0. significantly to 0. Counter-ions have been omitted omitted for clarity and en = ethylenediamine.62 ± 0. exhibits vitro in vitroofIC0. Fluorescence imaging experiments experiments utilising the lead compound in this series Pt10.2’-bipyridyl 6-phenyl-2. recently. Values In vitro taken from cytotoxicity references of Pt7. Fluorescence imaging have the potential to be activated via light irradiation (Figure 6). class of Pt9. DNA [40]. rectangular panels. IC values of >100 µM in the absence of light. Subsequent in vivo testingininvivo nude testing miceinimplanted nude mice with implanted NCI-460withshowed NCI-460tumour showed inhibition tumour inhibition by 60%by 60%no with with noside-effects reported reported side-effects [40]. however upon irradiation. however upon showed no damage to DNA in the absence of light. 6). 1818 6 of 16 Table 2. from Pt9. Subsequentpotent anticancer activity. 6.most Thecytotoxic complexcomplex most cytotoxic from thisfromclass this of compounds. (SH-5YSY). In vitro cytotoxicity of Pt7. this IC value decreased significantly to 0. carbon is cream/white cream/white and nitrogen is blue/purple. Pt7’.010 0.1 3.0065±± 0. Pt8[34.004 0. however.010 µM against oral oral epidermal epidermal carcinoma carcinoma (KB) and (KB) and neuroblastoma neuroblastoma (SH-5YSY).52 ± 0.38]. J.0002 – – 0.32 ± 0.01 0.9 – Figure Figure 5. revealed the compound selectively utilising the lead compound in this series Pt10.2 ± 0.50 . Pt10 is reported to interact with DNA via a dual binding mode involving nucleus. cells.9 – Pt8’ 2. 6. as determined through a solution structure (PDB 1XRW) [39].0065 0.These Thesecomplexes complexes have demonstratedthe have demonstrated theability abilitytotoform form emissive emissive exciplexes exciplexes with DNA with DNA via intercalation via intercalation[40].001 0.4 ± 0.2’-bipyridyl(Figure (Figure6).62 ± 0.0001 0. In vitro ovarian studies cancer (CP70)of Pt10 in cisplatin-resistant cell lines showed IC50 values human of >100 ovarian µM incancer the (CP70) cell lines showed absence of light. IC50 (µM) IC50 (µM) Complex Cell Line Complex Cell Line NCI-H460 NCI-H460 NCI-H520 NCI-H520 NCI-H522 NCI-H522 A549 A549 HL-60HL-60 Pt7 Pt7 0.043 ± 0.

due to its natural bioavailability. The progressed role of copper in the to phaseoxygen-dependentgrowth of II clinical trials [44. to the double strand [46–48].45]. Copperenough complexesthat most copper cancerous capturing tissues agents have[42.43]. Copper is very different also capable species of a large from reactions withvariety of coordination very similar geometries. its role in angiogenesis and increased uptake in Copper anticancer has a long agents. Copper Copper has a long history in medicinal inorganic chemistry. Cu2 and Cu3 where L is one of phen (Cu1). Structures of have copper complexes been Cu1–4. particularly in antibacterial and anticancer agents.SKOV3 human cancer cells (Figure 7). history in medicinal inorganic chemistry. starting reagents[46. Blue-coloured atoms are those that coordinate to the copper centre for each L example.due to its natural bioavailability. human and cancer each cells (Figure exhibited 7). Mol. be cytotoxic benzoate to HCT116 colorectal or o-. dpq (Cu2). All complexes could cleave plasmid DNA through an oxidative mechanism. 3. dppz (Cu3) or benzo[i]dppz (dppn. Figure 7) [49]. or [Cu(4phterpy)(L)(H For 4phterpy 2O)2](L) (where example a p-hydroxybenzoate. m. copper initiate capturing their cytotoxic agents effect have progressed through to phase II clinical oxygen-dependent or trials [44.43]. Pt9Pt9 andand the the tetraplatinated tetraplatinated porphyrin. Cu4. Cu4.47]. and the IC50 value of each complex in the SKOV3 human cancer cell line.45].2”-terpyridine and L is one of p-toluenesulphonate.45]. Figure 7. 2016. tissues [42. Counter-ions Counter-ions have have been been omittedomitted for for clarity. well-known types this ofscaffold was modified copper nucleases to afford are those additional phen incorporating complexes such asof [Cu(phen) the type [Cu(phen)(L)]. CT-DNA binding 60-hold demonstrated affinity thanhigher with binding Cu1CT-DNA bindingconstants affinity than Cu1 with3 × of approximately 10 M. Structures of copper complexes Cu1–4.Int. particularly in antibacterial and 3.most DNA DNA intercalation can assist the cleavage process by allowing close proximity of copper complexes often initiate intercalation can their cytotoxic assist effect through the cleavage process oxygen-dependent or -independent DNA complexes cleavage. 1818 7 of 17 Int. Here. Cu5–9. Figure 7) [49]. In a where study.2”-terpyridine and L is one of p-toluenesulphonate. Copper is also capable of a large variety of coordination geometries. Cu5–9. J. 17.47]. often The to the double strand [46–48]. dppz (Cu3) or benzo[i]dppz (dppn. 1818 7 of 16 Figure Figure 6. Here. The scope Counter-ions have been expands of copperhave nucleases omitted for clarity. low-micromolar approximately 3 × 10 M. Sci. this scaffold was modified to afford additional complexes of the type [Cu(phen)(L)]. dpq (Cu2). Mol. Here. for and the IC50 value of each complex in the SKOV3 clarity.2’:6’. 2 ] . producing very different most well-known types species of copper from reactions nucleases are with thosevery similar starting incorporating reagents[46. or HepG2 hepatocellular carcinoma cells while exhibiting lower activity in normal human fibroblasts 4phterpy is 4’-phenyl-2. J.2’:6’. thisLscaffold is one ofwas phen (Cu1).or HepG2 hepatocellular carcinoma cells while exhibiting lower activity in normal human fibroblasts . Intercalation was grooves. Inmost a often producing very different species from reactions with very similar starting reagents[46.or The scope series of of copper complexes of thenucleases expands far2]beyond type [Cu(4phterpy)(L) copper phenanthrenes. Copper is alsobycapable allowing of aclose largeproximity variety ofof copper coordination to the geometries. omittedCu1–4. natural The role bioavailability.43].additional to afford dppz (Cu3) or benzo[i]dppz complexes (dppn. Sci. example. Pt10. All complexes could cleave plasmid DNA through an oxidative 7 mechanism.47]. Counter-ions example. Structures of copper complexes and the IC50 value of each complex in the SKOV3 human cancer cell line. Structures of the luminescent cyclometalated PC. particularlyandinincreased antibacterial and cancerous tissuesdue to its [42. 17. 2 O) ](L) (where benzoate2 or2 o-.DNA -independent Copper complexes cleavage. 2+ The recent study. Counter-ions have been omitted for clarity. thanandCu1 Cu3with binding constants demonstrated of 60-hold higher Intercalation was theorised to occur within both the major and minor grooves. J. Structures 6. Mol. 7 activity and eachagainst SKOV3 exhibited human canceractivity low-micromolar cells (Figure against7). demonstrated theorised to occur60-hold within both higher CT-DNA the major binding and minor affinityCu2 grooves. dpq modified (Cu2). its role in angiogenesis and increased uptake in copper capturing agentsThe roleprogressed have of copper toin the phasegrowth of tumours II clinical is significant trials [44. Figure 8) were and L is found to one of p-toluenesulphonate. Cu2 and Cu3 approximately 3 × 10 7 M. 1818 7 of 16 Int. 17. Pt9 and the tetraplatinated porphyrin. For example a recent clarity. DNA double intercalation can assist the cleavage process by allowing close proximity of copper complexes often strand producing [46–48]. Blue-coloured atoms are those that coordinate to the copper centre for each L human cancer cell line. Counter-ions been omitted forfar beyond copper phenanthrenes. of the type Cu4. Pt10. Intercalation was theorised to occur within both the major and minor one of phen (Cu1).clarity.PC. m. porphyrin. tumours is significant Copper DNA complexes enough most that often often initiate their cytotoxic effect through or -independent cleavage. 2016. For example a recent is 4’-phenyl-2. Blue-coloured atoms are those that coordinate to the copper centre for each L Figure 7. phen such as [Cu(phen)2The ]2+. series of complexes of the type [Cu(4phterpy)(L)2] or [Cu(4phterpy)(L)(H2O)2](L) (where 4phterpy The scope of copper nucleases expands far beyond copper phenanthrenes. Copper 3. Figure 6.2”-terpyridine p-hydroxybenzoate. 7) [49]. In a recent most well-known types of copper nucleases are those incorporating phen such as [Cu(phen)2]2+. L is recent study. Figurewhere [Cu(phen)(L)]. Structures of the of the luminescent luminescent cyclometalated cyclometalated PC. 2016. Copper Copper has a long history in medicinal inorganic chemistry. Sci.and carcinoma m. Figure 8) were found to be cytotoxic to HCT116 colorectal carcinoma and recent series of complexes of the type [Cu(4phterpy)(L) ] or [Cu(4phterpy)(L)(H is 4’-phenyl-2.2’:6’. of copper in theitsgrowth role inofangiogenesis tumours is significant enoughuptake that in anticancer cancerous agents. Figure 7. Pt10. benzoate or o-. constants binding All complexes of and could each cleave exhibited plasmid low-micromolar DNA through activity an against oxidative SKOV3 mechanism.

low asHepG-2 andµM 0. and induce augmented tumour regression in a murine necessarily correlated for all complexes in the study [51]. the DNA binding and biological activity were not necessarily demonstrated potential as anticancer agents due to their efficient DNA binding and cleavage activity. was foundand induce augmentedand to intercalate tumour cleaveregression in a DNA. andandeach was each was capable capableofofhydrolytically hydrolytically cleaving cleaving plasmid plasmid DNADNA under underboth bothaerobic aerobicand andanaerobic anaerobic conditions conditions in ainradical a radicalandand oxygen-independent oxygen-independent manner. Sci.08Cu11 (Table µMmore were 3). the quantity Alternatively. Each cleavage complex through is capable an oxidative of intercalation mechanism involving and DNA cleavage hydroxide radicals through an oxygen. Mol. exhibit A micromolar-level bis-thiosemicarbazone activitycopper against complex HCT116 cells. Another recent study focused on a series of copper semicarbazone complexes: Another recent study focused on a series of copper semicarbazone complexes: [Cu(Bp4mT)(µ-Cl)] [Cu(Bp4mT)(µ-Cl)]2 (Cu10). the increased lipophilicity andby afforded it was proposed that the methylated the increased nitrogen lipophilicity of the Bp4mT ligand could increase afforded the passivenitrogen by the methylated diffusion ofof Cu10 the Bp4mTandligand Cu11 into could cancerous increase cells. dimer. DNA. Overall. Cu7 and Cu7 Cu8. transporters [50]. manner. Counter-ions Counter-ionshave havebeen beenomitted omittedfor forclarity. which could encourage cellular aqua ligands and charged nature. be at least tenand times more active NCI-H460 cells.Structures Structuresofofcomplexes complexes Cu5–13. be as a consequence of double the quantity of active There are many components other in the notable recent studies of intercalating copper nucleases [46. 8. copper intercalators have HCT116 cell xenograft model. the higher cytotoxicity of Cu9 relative to the others was theorised to be due to its labileto be due to its labile aqua ligands and charged nature. However. Cu5–13. cleavage. (Figure 8) [47]. Cu5–9. of active it could alsocomponents in the dimer. 2016. 2016. Sci. (Cu13) [Cu(µ-Bp4mT)Br] (where Bp4mT 2 (Cu11). J. activity against HeLa. the DNA binding and biological activity were not micromolar-level activity against HCT116 cells. the higher cytotoxicity of Cu9 relative to the others was theorised mechanism.01 0. and [Cu(HBpT)Br] 2 (Cu10).exhibiting exhibiting binding constants of binding constants of10 −1. All complexesintercalated intercalatedwith withDNA. Cu5. 17. exhibit murine HCT116 cell xenograft model.01 NCI-H460 (Table 3). 1818 8 of 16 HepG2 hepatocellular carcinoma cells while exhibiting lower activity in normal human fibroblasts (Table (Table 3) 3) [48]. which could encourage cellular uptake by human copper uptake by human copper transporters [50]. and HBpT is 2-benzoylpyridinethiosemicarbazone. produced Cu6Cu6 a substantial produced a substantialamount amountof linear of DNAlinear DNAcleavage during during cleavage experiments experiments relative relative to to Cu5. However. correlated for all complexes in the study [51]. MCF-7 and A549 cells and cleaved DNA without addition Two copper intercalators of (2-((quinolin-8-ylimino)methyl)pyridine) recently exhibited activity of peroxide [46]. J.Int.51–54]. Mol. clarity.51–54]. 17. MCF-7 and A549 cells and cleaved DNA without addition of peroxide [46]. .and that the ortho Cu8.cells. Figure 8) were found to be cytotoxic to HCT116 colorectal carcinoma and Int. Figure Figure 8.08 ± 0. more activeAll complexes than cisplatin were found against to HepG-2 HeLa. suggesting suggesting that the ortho of position theposition benzoate of hydroxyl the benzoate hydroxyl group group was was optimal optimal for DNA for DNA cleavage. Overall. achievingcomplexes The dinuclear IC50 values as Cu10 low asand ± 0. and [Cu(HBpT)Br] (Cu13) is 2-benzoylpyridine-4-methylthiosemicarbazone and(where HBpTBp4mT is is 2-benzoylpyridine-4-methylthiosemicarbazone 2-benzoylpyridinethiosemicarbazone. and singlet oxidative mechanism All complexesinvolving were hydroxide found to beradicals at least and singlet ten times oxygen. twice than The dinuclear as active complexes Cu10 andCu12 as the mononuclear Cu11andwere more Cu13. andthan twice it was as proposed active as thethatmononuclear Cu12 and Cu13. Alternatively. [48]. Two copper There are intercalators many other of (2-((quinolin-8-ylimino)methyl)pyridine) notable recent studies of intercalating copper recentlynucleases exhibited [46. A bis-thiosemicarbazone copper complex was found to intercalate against HeLa.TheThemodel modelcomplex Cu9 induced complexCu9 induced apoptosis apoptosis in in HCT116 HCT116cells cellsinina acaspase-3 caspase-3 related related mechanism. 1818 8 of 17 p-hydroxybenzoate. [Cu(HBpT)Cl] (Cu12).than cisplatin achieving IC50 against values asHeLa. [Cu(HBpT)Cl] (Cu12). the passive diffusionit of could Cu10 andalso Cu11be as a consequence into of double cancerous cells. and cleave DNA. All complexes 1055–10 –106 6MM −1 . copper intercalators have demonstrated potential as anticancer agents due to their efficient DNA binding and cleavage activity. [Cu(µ-Bp4mT)Br]2 (Cu11). Each complex is capable of intercalation and (Figure DNA 8) [47].

expressed as IC50 values with standard error (1significant figure).08 ± 0.5]-thiadiazolo-[3. Cisplatin is included as a reference.44 ± 0. .7 [a] NHF = normal human fibroblasts.5 ± 0.7 ± 0. expressed as IC50 values with standard error (1 significant figure). The most common type of ruthenium intercalators are polypyridyl complexes [Ru(L1 )2 (L2 )]2+ .4 2. While these types of complexes often display low levels of cytotoxicity.6 ± 0.16 ± 0. Ru1–3. Sci.2 0.07 ± 0.5 >20 Cu6 0.8 ± 0.10]phenanthroline. with the complex indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) successfully completing phase I clinical trials [57]. IC50 (µM) Complex Reference HCT116 HepG-2 NHF [a] Cu5 0.4-f ]-[1.10]phenanthroline.3 ± 0.09 0.00 ± 0.003 Complex HeLa HepG-2 NCI-H460 Reference Cu10 0.2 0.08 – – – Ru4 27 ± 2 [61] Cisplatin 15 ± 2 [61] Ru5 25 ± 2 [a] Values account for irradiation at 420 nm. In vitro cytotoxicity of complexes Ru1–7 in HeLa cells.483 ± 0.0 ± 0.04 0.31 ± 0. Table 4.Int.02 5.05 0. whereas the complex (ImH)[trans-RuCl4 (DMSO)(Im)] (NAMI-A. 1818 9 of 17 Table 3.1 >5 Cu9 0. with Ru4 being more active than Ru5 (Table 4) [61].0 ± 0. 2016.05 0. In a different study. or 2-phenyl-1H-imidazo[4.7 Ru3 19.24 ± 0.03 >5 [48] Cu8 1. there are several polypyridyl compounds recently synthesised that demonstrate potent activity. Figure 9) were shown to intercalate with DNA and cause cell cycle arrest in the A549 cell line at G0 /G1 phase. 17.10 ± 0.01 Cu11 0.01 [47] Cu12 1.1 ± 0.00 ± 0.10]-phenanthroline.The complexes also induced mitochondrial dysfunction and ultimately apoptosis involving ROS accumulation and Bcl-2 and caspase family activation. DMSO = dimethylsulphoxide) has progressed to phase II clinical trials [58]. A recent series of complexes of the type [Ru(L)2 (tdzp)]2+ (where L is one of bpy.0 ± 0.5 ± 0.1 Ru6 [a] 2.5-f ] [1. in which L2 is a long intercalating ligand such as dppz or dppn and L1 are two ancillary ligands that can affect DNA binding properties (Figure 6) [59].02 0. In vitro cytotoxicity of complexes Cu5–13 in various cell lines. These complexes accumulated within the nuclei of cells and were antiproliferative against HeLa cells (Table 4) [60].5 >20 Cu7 0.01 0.2 1. 4.16 ± 0.468 ± 0.4 ± 0.59 ± 0. complexes of the type [Ru(MeIm)4 (L)]2+ (where MeIm = 1-methylimidazol and L = 2-(4-chlorophenyl)-1H-imidazo[4. Mol. The cytotoxicity of each complex was comparable with cisplatin in several cell lines.20 ± 0.6 1.3 Cu13 1.03 14. Ru4.5 ± 0. Some ruthenium anticancer complexes have advanced to clinical trials.5-f ] [1.54 ± 0.006 13. phen or dpq and tdzp is [1.0 ± 0.9 [62] Ru2 21. and the inherent fluorescent properties and high kinetic stability of ruthenium compounds are extremely beneficial to biological studies [55].08 [60] Ru7 [a] 5. Ruthenium The octahedral geometry and interchangeable oxidation states of Ru(II) and Ru(III) allow for a large diversity of ligand combinations. where Im = imidazole. Ru5. J.2. as well as the design of photo-activated complexes [56]. Figure 9) were found to intercalate with DNA with binding constants of 103 –104 M−1 in a manner dependent on the planarity of ligand. Complex IC50 (µM) Reference Complex IC50 (µM) Reference Ru1 28.

Polypyridyl Figure also ruthenium 10)represented intercalated complexes as blue/purple with DNA rectangular have via the R-dppz panels. Chemical structures of ruthenium arene complexes Ru6–9.66]. 2016. irradiated with light at 420 nm (Table 4) [62].3-Dimethyl-4- “piano-stool” light-induced complexes acylpyrazolon-5-ato cytotoxicityare in ligands. Blue-coloured polypyridyl Counter-ions complexes have been atoms Ru1–5 are (left) omitted those and for the that X-ray clarity. base pairs. J. Sci. radicals. carbon and as blue/purple separates the is cream/white rectangular DNAnitrogen and panels. 7 cells (Ru9. 2016. Chemical structures of ruthenium polypyridyl complexes Ru1–5 (left) and the X-ray crystal Figure 9. Oxygen agents is orange. 1. Figure 10). the type [Ru(bpy) ruthenium-derived singlet 2(R-dppz)]2+ (where R is either NH2. 1818 10 of 17 Int. Mol. and some occurs studies through have a reported naphthoyl)-pyrazolon-5-ate)Cl] (Ru8. from PDB file 4JD8 [59].[63. [Ru(p-cymene)(1. through of >150Complexes both and 42. Ru6 or OMe. as well through both as light-induced cytotoxicity ruthenium-derived singlet oxygen in and F98 anthracene-derived glioma cells [65. Figure 10. against oxygenHeLaand anthracene-derived cells when irradiated radicals. Sci. Figure 10). phosphorous Complexes of theis yellow. 10) [68].3-dimethyl-4-(1-naphthoyl)-pyrazolon-5-ate)Cl] (Ru8.modeA polypyridyl photocleavage of DNA through bothand some studies ruthenium-derived have reported singlet a dual-binding oxygen in which and anthracene-derived ruthenation occurs through a leaving group while the p-cymene group intercalates betweenofnearby ruthenium complex incorporating an appended anthracene demonstrated photocleavage DNA radicals. andoccurs through abetween a leaving nearby chloroquine-tethered group bases complex while [67]. 2016. carbon is 2cream/white type [Ru(bpy) (R-dppz)]2+and nitrogen (where R isis blue/purple.The Ru6 base orpairs OMe. Figure Figure 10) [68]. Counter-ions have been omitted 10. either NH2.66]. Sci. 1818 10 of 16 Figure 9. Polypyridyl Figurecomplex ruthenium 10) complexes intercalated incorporating with an have DNA appended alsovia been the anthraceneused as intercalating R-dppz photodynamic ligand photocleavage demonstrated and achieved ofagents phototoxic DNA indices[63.very F98 prominent ofglioma whichcells anticancer the[65.3-Dimethyl-4-acylpyrazolon-5-ato include a series of complexes incorporating ligands. Ru7. A polypyridyl 2 OMe. Chemical structures of ruthenium polypyridyl complexes Ru1–5 (left) and the X-ray crystal structure of rac-[Ru(phen)2(dppz)]2+ bound to DNA sequence d(ATGCAT)2 (right). FigureFigure 10. is here shown withThe blue/purple. Sourced represented as blue/purple rectangular panels. incorporating Recent examples Figure 10) [68]. respectively. J.3-dimethyl-4-(1. of which the lead compound. Ru6 or respectively. demonstrated potent activity naphthoyl)-pyrazolon-5-ate)Cl] (Ru8. coordinate crystal Oxygen is to the ruthenium structure centre of in each rac-[Ru(phen) L example. [63. The base pairs are 2 for 2 clarity. Counter-ions have been for clarity. 17. Blue-coloured atoms are those that coordinate enantiomers Figure bound. 9. demonstrated potent activity against several cell againstlines several cell lines [67]. the blue-coloured oxygen or nitrogen atoms. and a chloroquine-tethered complex with submicromolar activity against A549 and MCF- A549 and MCF-7 cells (Ru9. Sourced from PDB file 4JD8 [59]. Ligands with a blue label coordinate at the “L” position of the arene through the omitted for clarity. are Ru7. Oxygen The is extended orange. as well with light as nm at 420 Figure 10) intercalated withinDNA via the cells R-dppz ligand and achieved phototoxic indices of >150 and (Table light-induced cytotoxicity 4) [62]. Figure 10).3-dimethyl-4-(1- (1. agents. La coordinates at the X2 position through the red nitrogen. 1818 10 of 16 Int. Mol. A polypyridyl F98 glioma ruthenium complex [65. against HeLa cells when irradiated with 2 light at 420 nm (Table 4) [62]. are a dual-binding very mode prominent in which anticancer ruthenation agents. Blue-coloured atoms are those that coordinate Polypyridyl to the ruthenium ruthenium centre incomplexes each L example. demonstrated potent activity against several cellleaving a group dual-binding while mode the in p-cymene which ruthenation grouplines intercalates [67]. [Ru(p-cymene)1. have Counter-ions also been used haveasbeen intercalating omitted forphotodynamic clarity.64]. Recent examples include a series of complexes incorporating 1. ruthenium Ru7. Ruthenium incorporating anarene “piano-stool” appended anthracenecomplexes are demonstrated 42.66]. Ruthenium lead compound. Complexes of the type [Ru(bpy) (R-dppz)] 2+ (where R is either NH . carbon is cream/white and nitrogen is blue/purple. (right). Chemical to the ruthenium Sourced centre from structures in ofPDB each file 4JD8 ruthenium L example. La coordinates at the X2 position through the red nitrogen.Ruthenium as well as arene bases [67]. . 17. both the pairs base ∆ and areΛ also enantiomers bound. J. Ligands with a blue label coordinate at the “L” position of the arene through blue-coloured oxygen or nitrogen atoms. here shown with both the ∆ and Λ enantiomers bound. 7 cells (Ru9. of which the lead compound. aromatic phosphorous also isligand represented intercalates yellow. and arene some studies “piano-stool” have reported complexes [Ru(p-cymene)(1. (dppz)] Counter-ions 2+ bound to DNA have sequencebeen omitted d(ATGCAT) orange. Mol.64]. and a chloroquine-tethered complex with submicromolar activity against [67].also ligandbeen used as and achieved intercalating phototoxic indices ofphotodynamic >150 and agents42. La coordinates at the X2 position through the red nitrogen. 17. Chemical structures of ruthenium arene complexes Ru6–9.3-Dimethyl-4- acylpyrazolon-5-ato ligands. Chemical structures of ruthenium arene complexes Ru6–9.64].of respectively. here shown with both the ∆ and Λ aromatic ligand intercalates and separates the DNA base pairs. phosphorous is yellow. with the Recent p-cymene examples submicromolar group intercalates include activity against between a series A549 and ofnearby complexes MCF- bases [67]. The extended structure of rac-[Ru(phen)2 (dppz)]2+ bound to DNA sequence d(ATGCAT)2 (right). The extended aromatic ligand intercalates and separates the DNA base pairs. Counter-ions have been omitted for clarity. very prominent against anticancer HeLa cells when agents.Int. [59]. Ligands with a blue label coordinate at the “L” position of the arene through the blue-coloured oxygen or nitrogen atoms.

[69–71]. J. The lead compound.78]. Another binding studyAnother to Top1 itself. The hypothesised mechanism of action of cell lines.13. activity.13. the metallointercalators Fe1. J. Here occurred inhibitionthrough intercalative occurred through binding to thebinding intercalative DNA substrate to the DNA of Top1 and not substrate through of Top1 andbinding to Top1 not through itself. 17.9:18.21-diepimino[1. Mol. [Au(12. activity was exhibited low micromolar bywas activity the four complexes exhibited by theinfour HT-29 and MCF-7 complexes cell lines. Figure 11) demonstrated low micromolar activity in a variety of cell lines. gold complexes have been relatively successful in medicinal chemistry [69–71]. 1818 11 of 17 Int. resulting in elevated levels of phosphorylated p53 gene and apoptosis. Additionally. Figure 11) was highly active against MCF7 cells 2-oxoindolin-3-ylidene)-N-methylhydrazinecarbothioamide. [Au(12. resulting in elevated levels of phosphorylated p53 was DNA damage via intercalation and cleavage.15-tetrahydro-6. iron most commonly exists in two oxidation states (Fe(II) and (Fe(III)).8% cleavage of plasmid DNA addition of peroxide [78]. Other OtherMetals Metals A large spectrum spectrum of of transition transitionmetal metalcomplexes complexeshavehave been been used used asas anticancer anticancer agents.21-diepimino[1. Zn1 Au1.Int. 2016. Another intercalating zinc complex of 5-bromo-8-hydroxyquinoline displayed higher cytotoxicity in BEL-7404 and T-24 cells than cisplatin and induced cell cycle arrest in the G2 higher cytotoxicity in BEL-7404 and T-24 cells than cisplatin and induced cell cycle arrest in phase of the BEL-7404 cells [79]. Zn1 and and Ni1. For example. study focused upon complexes 2+of 2.3 µM against MCF-7 cells. molecular modelling and surface plasmon resonance studies revealed that Au1 waswasanan inhibitor of human inhibitor of humantopoisomerase 1 (Top1). All complexes in the study cleaved Here the nickel complexes were generally more active than the cobalt [80]. . with in IC50 of 2. Another intercalating zinc complex of 5-bromo-8-hydroxyquinoline displayed gene and apoptosis. [Ni(L)2 ] (where L = (Z)-2-(1-benzyl- ylidene)-N-methylhydrazinecarbothioamide. nickel and cobalt complexes of the anaesthetic MCF7 cells with an IC50 value of <0. complexes were generally more active than the cobalt [80]. Structures Structures of of the metallointercalators Au1. cleaved plasmid DNA in the presence of H2 O2 in a singlet oxygen-involved method.3 µM against MCF-7 cells. Here the nickel the anaesthetic lidocaine produced low micromolar IC50 values against a panel of human cell lines. were designed as The complexes dual-action were designed anticancer as dual- agents that both intercalate action anticancer agents thatwithbothDNA and inhibit intercalate thioredoxin with DNA reductase and inhibit activity.6]diazacycloctadecino[12. particularly in leukaemia and central nervous system cancers. [72–74].8-naphthalimide centre tethered to through an N-heterocyclic a gold centre carbene moietycarbene through an N-heterocyclic [76]. Figure 11. and was well-tolerated by nude nude tumour-less tumour-less mice mice at at high high doses.13-b]quinoxaline)]+ + (Au1. In an additional study. [Ni(L)2] (where L = (Z)-2-(1-benzyl-2-oxoindolin-3- without the addition of peroxide [78]. A series of nickel isotin thiosemicarbazone complexes were also the G2 phase of the BEL-7404 cells [79]. doses. focused on gold(I) study complexes focused consisting on gold(I) complexes of aconsisting DNA intercalating of a DNA1.9 ± 0. thioredoxin low micromolar reductase activity. in HT-29 and MCF-7 cell lines.9:18. 2016.78]. Iron has also been exploited in the development of anticancer agents as it is an essential component of various biological processes including erythropoiesis.1 µM. with in IC50 of 2.8-naphthalimide tethered to a gold intercalating 1. The lead compound [Zn(bpbp)2] (Zn1. Sci. 17.6]diazacycloctadecino[12. although although for for manymany intercalation intercalation is not is not required required forforactivity. Figure 11) was highly active against with an IC50 value of <0. The lead compound. compound. Figure 11) demonstrated low micromolar activity in a variety The lead compound [Zn(bpbp)2 ]2+ (Zn1. electron transport and DNA synthesis [81]. The hypothesised mechanism of action was DNA damage via intercalation and cleavage. A recent zinc to their natural abundance in humans and important roles in cellular functions [77. Enzyme inhibition assays. agents. A series of nickel isotin thiosemicarbazone complexes found to intercalate with DNA and achieve up to 99. Counter-ions Counter-ions have have been been omitted for clarity. Nickel and zinc have also seen widespread use in medicinal chemistry as DNA nucleases due to Nickel and zinc have also seen widespread use in medicinal chemistry as DNA nucleases due their natural abundance in humans and important roles in cellular functions [77. Fe1.9 ± 0.14. Sci.Nonetheless Nonethelesssome somerecent recentexamples examplesof of less common transition metal intercalators transition metal intercalators have have emerged emerged in the literature. although most active anticancer complexes do not target DNA [72–74].8% cleavage of plasmid DNA without the were also found to intercalate with DNA and achieve up to 99. Figure 11. Recently reported macrocyclic gold(III) complexes that incorporated a quinoxaline moiety moiety to promote promote DNA DNA intercalation intercalation demonstrated demonstrated cytotoxic cytotoxic activity activity [75]. omitted for clarity. Mol.14.1 µM.6-bis(1-phenyl-1H-benzo[d]imidazol-2-yl)pyridine (bpbp) [77].15-tetrahydro-6. topoisomerase 1 Here inhibition (Top1).13-b]quinoxaline)] Figure 11) 11) exhibited exhibited low low micromolar micromolar activity in a panel of human cell lines.6-bis(1-phenyl-1H-benzo[d]imidazol-2-yl)pyridine (bpbp) [77]. All complexes in the study plasmid DNA in the presence of H2O2 in a singlet oxygen-involved method. Ni1. A recent zinc study focused upon complexes of 2. Ni1. nickel and cobalt complexes of lidocaine produced low micromolar IC50 values against a panel of human cell lines. 1818 11 of 16 5. Ni1. The complexes moiety [76]. In an additional study. TheThe lead compound.

1818 12 of 17 Iron has also been exploited in the development of anticancer agents as it is an essential component of various biological processes including erythropoiesis. Ruthenium polypyridyl and arene complexes have exhibited micromolar activity against several human cell lines and some have proven potential as photoactivated drugs. Loehrer. Benjamin J. The huge variety of transition metal properties and ligand combinations has produced an extremely broad spectrum of intercalating anticancer complexes. with the primary aim of overcoming the drawbacks of currently used metallodrugs. A recent series of iron-based complexes that incorporate ferrocene as part of a modified tamoxifen base structure have been reported (Figure 11). Mol.H. T. Fe1.04 µM against human colon cancer (HCT-8) and acute promyelocytic leukaemia (HL-60). Christopher P. Frost for the contribution of the graphical abstract. showed no activity against non-cancerous glomerular basement membrane (GBM) monkey cells. externalisation of phosphatidylserine and increased DNA fragmentation. electron transport and DNA synthesis [81]. Pages and Dale L. The continued expansion of this spectrum has great potential to reveal metallointercalators which can outperform current metallodrugs and provide more effective chemotherapy.. Ang were supported by an Australian Postgraduate Award. which allows it to participate in important redox reactions [82]. each with a unique mechanism of action. however exhibited low micromolar activity in cancerous cell lines with IC50 values of 0. Med. Benjamin J. P. Conflicts of Interest: The authors declare no conflict of interest. 2016.J.. Nature 1965. Aldrich-Wright fulfilled similar duties to Christopher and also contributed to the “Ruthenium” section. Deo wrote the “Introduction” and “Platinum” sections. van Camp. We also thank Samuel J. Additionally. Gordon extensively revised the paper and provided many helpful suggestions regarding figure and paragraph layout as well as spelling and grammar checks.9 and 1. Copper complexes can intercalate and cleave DNA. Pages organised the content of the paper and wrote the “Copper” and “Other Metals” section. A variety of transition metal-based intercalators have been reviewed here. as well as the iron portion of “Other Metals”. Janice R. Nickel and zinc intercalators are also proven to be efficient DNA nucleases. and some have also demonstrated some tumour-inhibition results in vivo. L. Ang were additionally supported by a Western Sydney University Top-Up Award. Intern. 1984.Int. an extensive catalogue of metal complexes have been synthesised and evaluated as potential anticancer agents. Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Benjamin J. which were attributed to an intercalative mode of binding of Fe1 with dsDNA and ssDNA [83]. all of which are potently cytotoxic and demonstrate DNA intercalation. aside from the iron portion. Dale L. Krishant M. and contributed to the “Ruthenium” section. Recent pairing of intercalating ligands with other metals such as gold and iron has produced even more cytotoxic complexes with distinctly different mechanisms to kill cancerous cells. Conclusions Over the past five decades.. Ang researched and rendered several versions of the DNA PDB files. [CrossRef] [PubMed] 2. 698–699. Pages and Dale L. [CrossRef] [PubMed] . Deo. 205. Drugs five years later. respectively [83]. Mechanistic studies revealed the activation of caspases 3 and 7. B. J. Einhorn. Transition metal intercalators have been studied since the 1970s as alternatives that exerts cytotoxicity through different modes of action to cisplatin-like chemotherapeutics. Rosenberg. iron most commonly exists in two oxidation states (Fe(II) and (Fe(III)). L. Platinum intercalators can kill cancerous cells via unconventional methods at nanomolar concentrations. Author Contributions: Krishant M. 100. 17. Cisplatin. 704–713. Sci. Acknowledgments: The authors would like to thank Western Sydney University for financial support through internal research grants. Ann. References 1. with recent studies reporting potent compounds both with the phenanthrene architype coordination and without. 6. Krigas. The lead compound.

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