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ScienceDirect Metal-based anticancer chemotherapeutic agents Nafees Muhammad and Zijian Guo Since the discovery of the cisplatin antitumor activity, great efforts have focused on the rational design of metal-based anticancer agents that can be potentially used in cancer chemotherapy. Over the last four decades, a large number of metal complexes have been extensively investigated and evaluated in vitro and in vivo, and some of them were at different stages of clinical studies. Amongst these complexes, platinum (PtII and PtIV), ruthenium (RuII and RuIII), gold (AuI and AuIII) and titanium (TiIV) complexes are the most studied metals. We describe here some most recent progresses on PtIV prodrugs which can be activated once enter tumor cells, polynuclear PtII complexes which have unique DNA binding ability and mode, anti-metastatic RuII/RuIII complexes, and AuI/AuIII and TiIV antitumor active complexes. The key focuses of these studies lie in finding novel metal complexes which could potentially overcome the hurdles of current clinical drugs including toxicity, resistance and other pharmacological deficiencies. Addresses State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China Corresponding author: Guo, Zijian ([email protected]) Current Opinion in Chemical Biology 2014, 19:144–153 This review comes from a themed issue on Bioinorganic chemistry Edited by Elizabeth M Nolan and Mitsuhiko Shionoya
1367-5931/$ – see front matter, # 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cbpa.2014.02.003
Introduction The modern use of transition metal complexes as chemotherapeutic agents dates back to the serendipitous discovery of cisplatin by Rosenberg et al. in 1965 [1]. Such a discovery opened the gate of unexplored world of metal-based chemotherapeutic agents which have different kinetics and mechanism of action from those of conventional organic drugs [2]. Cisplatin, carboplatin and oxaliplatin are FDA approved platinum anticancer drugs that are used in clinic world-wide for the treatment of various cancers, while nedaplatin, lobaplatin, and heptaplatin are approved for clinical use respectively in Japan, China and Korea (Figure 1). However, side effects, toxicity and drug resistance are the major obstacles for wider clinical application of these drugs [3]. Bioinorganic and medicinal chemists are exploring different strategies to overcome the problems, which Current Opinion in Chemical Biology 2014, 19:144–153
includes targeted delivery of clinical drugs [4,5] and design of novel platinum and non-platinum metal complexes which have different structural features and reactivities [6]. Because of the excellent review coverage on the chemistry, biology and medicine of PtII-based anticancer drugs, in this short review we concentrate on some most recent advances on PtIV prodrugs, polynuclear PtII complexes, and RuII/III, AuI/III and TiIV-based anticancer complexes.
Pt(IV) prodrugs: a strategy to reduced toxicity and drug resistance PtIV complexes came into the medicinal stage soon after the toxicity of cisplatin became a major clinical issue for cancer treatment. It is believed that octahedral PtIV complexes are kinetically more inert in blood stream but can be activated once enters into the cells by reducing agents to give cytotoxic PtII species, offering potential advantage over PtII compounds regarding oral availability, reduced drug resistance and toxicity. Following the early efforts of Rosenberg and co-workers on PtIV analogues of cisplatin [7], thousands of PtIV complexes have been synthesized and evaluated in the context of prodrugs. The rationales behind the design of PtIV complexes are the fine tuning of their redox potential, kinetic stability, hydrophilicity/lipophilicity to achieve desired reactivity and activity through selection of axial and equatorial ligands. Two best known examples are satraplatin (1) (formally known as JM216) and LA-12 (2) [8]. Satraplatin 1 was once in the advanced stage of clinical trials for prostate, lung and ovarian cancers. It can be orally active, unlike other PtII drugs which have to be given intravenously. As a prodrug, 1 is activated by reduction in the presence of intracellular reducing agents such as glutathione, ascorbic acid, among others [9], and demonstrates little nephrotoxicity, neurotoxicity and ototoxicity. Complex 2 is an analogue of 1 and contains a bulky hydrophobic ligand, adamantylamine which could potentially increase the uptake of 2 by the cancer cells. Complex 2 was significantly more efficient than cisplatin against cisplatin resistant ovarian carcinoma A2780cisR cells, causing the increase of p53 level and cell cycle perturbations [10]. Wilson et al. synthesized a series of PtIV carbamate complexes (3–5) by reacting various alkyl and aryl isocyanates with PtIV hydroxy complex [Pt(NH3)2Cl2(OH)2] [11]. Slightly higher reduction potentials were found for the aryl carbamate complexes than for the alkyl carbamate complexes, which can be correlated with computed adiabatic electron affinities. All these complexes show equivalent or higher cytotoxicity than cisplatin against human www.sciencedirect.com
Metal-based anticancer chemotherapeutic agents Muhammad and Guo 145
Figure 1
H2N
O
Cl
H2N
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H2N
Cl
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H N
O O
N H
O Cis-Platin
HN HN
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H N NH3 Pt H3N Cl
4 4NO3-
BBR3464 Current Opinion in Chemical Biology
Clinically approved PtII drugs and complexes evaluated in clinical trials.
lung carcinoma A549 cells. In addition, compounds 4 and 5 that contain tert-butyl and cyclopentyl based carbamate ligands showed higher cytotoxicity than other complexes of this series. It is worth to mention that these complexes show higher cytotoxicity against cancer cells than normal cells such as normal lung MRC-5 cells. Medrano et al. [12] have synthesized two trans-PtIV phosphane complexes 6 and 7 to take advantage of the lipophilicity of phosphane group. Both complexes contain aliphatic amines trans to phosphane ligands, which enhances the stability of PtIV complexes. Both 6 and 7 are stable in solution and have IC50 values similar to that of cisplatin against carcinoma cell lines NCI-H460 and metastatic melanoma A375. Interestingly, both complexes were shown to be more selective and cytotoxic than that of cisplatin against HCT116 cells absent of wildtype p53 (HCT116 / cells). By tethering lipophilic carboxylate ligands in the axial position, Varbanov et al. have prepared a series tetracarboxylate PtIV complexes which demonstrate potent cytotoxicity against a variety of cancer cell lines (8, Figure 2e) [13]. It was concluded that both the reduction potential and the rate of reduction has major influences on the cytotoxic properties of these complexes and their amide/ ester derivatives. Another series of dicarboxylated PtIV complexes 10–12, which were developed by Ravera et al. [14], were based on picoplatin (Figure 1), an active PtII antitumor agent able to circumvent acquired Pt-chemotherapy resistance. The presence of a sterically demanding 2-methylpyridine in picoplatin hinders the www.sciencedirect.com
axial approach of GSH to the platinum center without detriment of the level of DNA platination. These complexes demonstrated potent activity against several different tumor cell lines sensitive and resistant to cisplatin. Interestingly, the cytotoxicity and selectivity of these complexes against resistant cell lines increases with the elongation of the axial chain. Pichler et al. [15] have recently synthesized a series of symmetrically and unsymmetrically substituted PtIV complexes containing various bulky groups at the equatorial position (e.g. 13–15). These bulky groups were found to play a major role in determining the stability and reaction patterns of the PtIV complexes. All these complexes show strong inhibitory effect against different tumor cell lines sensitive and resistant to cisplatin. An interesting correlation between the cytotoxicity and the lipophilicity of the complexes was proposed, although it is neither strong nor strictly linear, and has some exceptions. Selective photoactivation of PtIV complexes in cancer cells might avoid toxic side effects and extend their application to cisplatin resistant cells. Farrer et al. [16] reported a trans di-pyridine complex 16 which can be phototoxic against a number of human carcinoma cells when irradiated with UVA and visible light. This diazido complex is stable in solution and particularly inert toward GSH. The pyridine ligands appear to remain strongly bound to platinum, even after photoactivation. It seems clear that the molecular pharmacology of the photoactivatable excited state PtIV complex 16 is quite distinct from that of ground-state PtIV complexes. Current Opinion in Chemical Biology 2014, 19:144–153
146 Bioinorganic chemistry
Figure 2
O
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Cl Cl Pt Cl Cl NH H3C CH CH3 (7)
O N
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O NH3 Cl Pt NH3 Cl O
Pt Pt Pt Pt PtPt Pt Pt
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Pt@NP-GDfk Current Opinion in Chemical Biology
PtIV prodrugs. (a) Orally bioavailable satraplatin or JM216 (1). (b) LA-12, an analogue of satraplatin (2). (c) PtIV carbamate complexes (4 and 5). (d) trans-PtIV phosphane complexes (6 and 7). (e) Tetracarboxylate PtIV complex (8). (f) Picoplatin based dicarboxylated PtIV Complexes (10–12). (g) PtIV complexes with various bulky groups at the equatorial position (13–15). (h) Photoactivated trans di-pyridine PtIV complex (16). (i) Fluorescently labeled PtIV compound (17). (j) Acid responsive polymer drug conjugate, where n = 400–450 (18). (k) Targeted delivery of PtIV prodrug through RGD modified delivery vehicle.
Fluorescently labeled PtIV compounds can be potentially used in live cell imaging to monitor PtIV reduction. Song et al. [17] designed fluorescent PtIV prodrugs such as 17 by tethering fluorescein-derived ligands at the axial Current Opinion in Chemical Biology 2014, 19:144–153
position of dihydroxido PtIV precursors. The fluorescence of the ligands is quenched when bound to PtIV center. However, the reduction of 17 by biological reductants such as GSH or ascorbate results in the release of www.sciencedirect.com
Metal-based anticancer chemotherapeutic agents Muhammad and Guo 147
fluorescent ligands which consequently restores their fluorescence. These complexes can be potentially utilized to study intracellular reduction of PtIV prodrugs. The development of nano-carriers and nano-vehicles has recently gained very much attention for safer and targeted delivery of anticancer drugs [4,5]. The two axial positions in PtIV prodrugs offer great synthetic flexibility for further chemical modification and conjugation with nanomaterials. As a consequence, the therapeutic efficacy of PtIV prodrugs can be improved. For example, Aryal et al. have synthesized acid responsive polymer nanoparticles consisting of covalently linked polymer PtIV conjugate 18 (Figure 2j) [18]. The presence of hydrazone bond in 18 gives a highly differential drug release profile at different environmental acidity. During nanoparticle circulation in the blood, where the pH value is neutral, 18 is stable. However, upon its endocytosis by the target cells, where the pH value is acidic, rapid intracellular drug release is triggered. Kolishetti et al. [19] have synthesized selfassembled aptamer conjugated PLA nanoparticles for targeted delivery or co-delivery of cisplatin, PtIV prodrug and docetaxel to the prostate cancer cells. Similarly, Xiao et al. [20] reported a composite micelles containing both PtIV prodrug and paclitaxel. A synergetic effect of two therapeutic drugs was observed at both in vitro and in vivo experiments. A polymeric NP system comprising an encapsulated PtIV prodrug and cyclic RGD peptides (Figure 2k) as integrin targeting moieties has been developed for anticancer therapy [21].
Multinuclear platinum(II) complexes: unique DNA binding mode and ability Polynuclear PtII complexes represent a new class of anticancer agents that possess potent and distinct biological activity from cisplatin [22]. One of the most successful compounds is BBR3464 (Figure 1) which was once in Phase II clinical trials for the treatment of patients with melanoma, pancreatic, lung, ovarian and gastric tumors [23]. The complex is composed of two monofunctional Pt moieties, and the two separated Pt–Cl bonds maintain the bifunctional binding mode on DNA and form long range cross-linking adducts. Multinuclear PtII complexes offer different reactivities and biological activities from those of cisplatin and its analogues. Cytotoxic trinuclear complex 19 (Figure 3a) contains three monofunctional Pt–Cl motifs bridged by a bis(pyridylmethyl)amine ligand [24]. It demonstrated unique binding features to protein and DNA. For example, it interacts with human serum albumin at the hydrophobic cavity of domain II mainly through non-covalent actions [25]; it binds to DNA forming unique trifunctional intrastrand cross-linking adducts [26]. When two cisplatin moieties were bridged by aromatic linkers of different length, cytotoxic complexes 20 and 21 were obtained. Both complexes form preferentially inter-strand DNA www.sciencedirect.com
cross-linking adducts which can be recognized and bound strongly by high-mobility-group-domain proteins [27]. These complexes induce some cellular responses different from those caused by cisplatin. For example, they arrest the cell cycle in G2 or M phase, while cisplatin arrests the cell cycle in S phase; there are evidences that their cytostatic activity is closely associated with the activation of signaling pathways such as phosphoERK1/2 and phospho-p38 MAPK [28]. Komeda et al. have developed dinuclear PtII complexes using tetraazolate as a bridging ligand [29]. Complex 22 was formed at higher ratio than its isomer 23 probably due to the higher nucleophilicity of N1 or N4 bound to one C and one N atom, compared with N2 or N3 bound to two N in tetraazolate ligand. These complexes demonstrated potent activity against selected tumor cell lines and xenografts. The same group has extended their study to complexes with tetrazole ligands modified at C5 position (Figure 3d). Cytoxicity screening illustrates that the tailoring groups have an important impact on their activity. Among them 27 showed remarkable antitumor efficacy against pancreatic PANC-1 xenograft in nude mice [30]. These complexes offered a diverse skeleton for the design of novel antitumor complexes. Brown et al. reported a series of sterically hindered dinuclear PtII complexes such as complex 29 with bispyridyl based ligands containing diaminoalkanes of different lengths [31]. It is hypothesized that these complexes could combine the advantages of picoplatin (inert to sulfur nucleophiles) and BBR3464 (long range DNA cross-links). The cytotoxicity of these complexes was evaluated against human ovarian carcinoma A2780 cells and its cisplatin resistant cell lines. This work provides a proof-of-concept for the development of a larger family of sterically hindered multinuclear-based platinum complexes.
Ruthenium anticancer complexes: antitumor metastasis and overcome cisplatin resistance Ruthenium has several oxidation states (RuII, RuIII and RuIV) which can be tunable under physiological conditions. Ruthenium complexes have the same kinetic spectrum of ligand substitution as that of PtII complexes in aqueous medium, therefore are suitable alternative to PtII anticancer drugs. In the past few decades, several ruthenium (RuII and RuIII) complexes were developed and studied for their antiproliferative activities against various tumor models, but a real breakthrough comes from the development of NAMI-A (30) and KP1019 (31) (Figure 4a) ruthenium compounds which are now under clinical trials. These complexes are particularly useful for the treatment of metastatic tumors or cisplatin resistant tumors. Both of these complexes are structurally similar to each other but having a different cytotoxic profile toward the tumor cells. For example, 30 shows Current Opinion in Chemical Biology 2014, 19:144–153
148 Bioinorganic chemistry
Figure 3
(a)
(b)
+3
+2 Cl N Pt N
N N Pt N
Cl
H3N
Cl
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R= CH3, a= 2 R= C6H5, a= 2 R= CH2COOC2H5, a= 2 R= CH2COO-, a= 1
(24)
(23)
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+2 H3N O R
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+2
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N
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N NH3
NH3
H N n
N H
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N
R
O
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Multinuclear platinum complexes. (a) Trinuclear PtII complex containing three monofunctional Pt-Cl motifs (19). (b) Dinuclear PtII complexes connected by aromatic linkers (20 and 21). (C) Dinuclear PtII complexes with tetraazolate as bridging ligand (22 and 23). (d) Dinuclear PtII complexes with tetrazole ligands modified at C5 position (25–28). (e) Dinuclear PtII complex with bis-pyridyl based ligands (29).
little activity against primary tumors but found to be highly active against secondary tumors such as non-small cell lung cancer and inhibits the lung metastases, while KP1019 (31) shows potent cytotoxicity against primary tumors especially in colorectal cancer which is resistant to cisplatin chemotherapy. It should be noted that both complexes are only moderately active in vitro but is better tolerated in vivo and in clinical applications [32]. Solubility, tumor targeting and absorption are major issues concerned in the design of novel ruthenium complexes. Lakomska et al. have developed two RuIII complexes (Figure 4b) based on triazolopyrimidine ligands [33]. By introducing bulky substituents in the heterocyclic Current Opinion in Chemical Biology 2014, 19:144–153
ligands, the cytotoxicity of both complexes is significantly enhanced. For example, 32 and 33 show much higher cytotoxicity than that of cisplatin against human lung carcinoma A-549 and T47D breast carcinoma cell lines with IC50 values in the range of 0.02–2.4 mM range. The authors correlated the high cytotoxicity of these complexes to their high lipophilicity which is generally believed to facilitate cellular uptake. Pierroz et al. have synthesized a series of RuII polypyridyl complexes which are coordinatively saturated and substitutionally inert [34]. Among these complexes, 34 was found to have IC50 values comparable to cisplatin against several different cancer cell lines and better activity www.sciencedirect.com
Metal-based anticancer chemotherapeutic agents Muhammad and Guo 149
Figure 4
(b)
(a)
(30) (31) (c)
(32)
(33) (e)
(d)
(35) = Phen (36) (34) (g)
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(39) (j)
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(40)
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44 L1,2. R= p-NO2, R’= o,p-Cl 45 L1,3. R= p-NO2, R’= o,p-Br 46 L1,1. R=R’= p-NO2 47 L2,2. R=R’= p-Cl 48 L3,3. R=R’= o,p-Br
(42) 50 R= 4-Cl 51 R= 2-Cl (49) Current Opinion in Chemical Biology
Ruthenium, gold and titanium based anticancer complexes. (a) Ruthenium based drugs in clinical trials NAMI A (30) and KP1019 (31). (b) RuIII complexes based on triazolopyrimidine ligands (32 and 33). (c) RuII polypyridyl complex (34). (d) RuII complex comprises of mixed ligand (35). (e) Mitochondrial targeted mixed ligand based RuII complex (36). (f) RuII-arene complexes (37). (g) AuI/AuIII complexes with imidazolate derivatives (38–40). (h) AuIII complexes with N-heterocyclic carbene ligands (41 and 42). (i) AuIII-dithiocarbamate complex (43). (j) Symmetrical TiIV-Salan complexes (44–48). (k) Trans-TiIV complexes consisting of salophen ligand (50 and 51).
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150 Bioinorganic chemistry
against cisplatin-resistant cell line than cisplatin. Complex 34 was found to target the mitochondria of cancer cells and induce mitochondrial mediated apoptosis. Interestingly, subtle structural changes can have a significant impact on both the cytotoxicity and cellular localization of this series of complexes. When the 4-carboxylic acid group in 34 was replaced by a hexanoic acid group, the RuII complex loses the cytotoxicity and targeting property. Li et al. synthesized a series of RuII complexes containing bis-benzimidazole derivatives, and introduced phenathroline as a mixed ligand for comparison [35]. These complexes were screened against a series of tumor cell lines and a normal human fibroblast (HS68) cell line. Among them, complex 35 shows selective cytotoxicity against tumor cell lines but very little toxicity against Hs68 normal cells. It induces caspase-dependent apoptosis in cancer cells through overproduction of superoxide. Qian et al. revealed that mixed ligand RuII complexes such as 36 exhibit potent activity against a variety of tumor cell lines [36]. Complex 36 accumulates preferentially in the mitochondria of HeLa cells and induces apoptosis via the mitochondrial pathway, which involved ROS generation, mitochondrial membrane potential depolarization, and Bcl-2 and caspase family member activation. Sadler, Dyson and others have developed a series of RuIIarene based antitumor active complexes [37,38]. These organometallic complexes are remarkably stable in biological media and can be recognized by various biotargets. They often have amphiphilic properties and are very active against a variety of tumor models [39,40,41]. RuII-arene system (37) offers a rich platform for incorporation of a variety of functional groups at either the metal center or arene moiety [42].
Gold and titanium anticancer complexes: multiple targets In the last few decades, many AuI and AuIII compounds with different molecular structures have been developed and tested as anticancer agents. Gold complexes with phosphine and carbene ligands, dithiocarbamates, porphyrinates have been among the most widely investigated in vitro and in vivo [43]. Although the molecular mechanism of action remains to be elucidated, some relevant biochemical properties of gold complexes are shared in common. For example, the inhibition of thioredoxin reductase (TrxR), DNA and protein binding, the triggering of antimitochondrial effects and the induction of apoptotic events, among others have been confirmed for different gold compounds, which contributes to their pharmacological profiles [44]. Serratrice et al. reported a series of AuI/AuIII complexes with imidazolate derivatives such as 38, 39 and 40 (Figure 4g) [45]. These complexes were evaluated against Current Opinion in Chemical Biology 2014, 19:144–153
ovarian and breast carcinoma cell lines, and the AuI dinuclear complexes 39 and 40 showed higher cytotoxicity than cisplatin. Notably, most of the tested AuI/AuIII complexes demonstrated higher cytotoxicity than cisplatin against cisplatin resistance ovarian cancer cells, which indicates a different mechanism of action for gold complexes. Zou et al. reported a series of AuIII complexes with Nheterocyclic carbene Ligands [46]. These complexes can be used as both thiol ‘‘switch-on’’ fluorescent probes and anti-cancer agents. For example, when AuIII in complex 41 is reduced to AuI by biological thiols such as glutathione or cysteine fluorescent ligand is released, which gives a 200-fold emission enhancement. Complex 42 demonstrated highest in vitro cytotoxicity among the tested complexes, therefore it was further evaluated in vivo using nude mice bearing HeLa xenografts. Significant reduction in tumor volume was observed. Ronconi et al. have proved that AuIII-dithiocarbamate complexes can be promising anticancer agents owing to their interesting in vitro and in vivo cytotoxic activity combined with negligible toxic side-effects [47]. Deubiquitinases, a family of proteases that regulate the ubiquitin system by specifically hydrolyzing isopeptide or peptide bonds between ubiquitin and its conjugated proteins, can be potential target for organometallic AuIII-dithiocarbamate complexes [48]. For example, complex 43 showed 55% inhibition of deubiquitinases in breast carcinoma MCF7 cells in a time dependent manner. It is more cytotoxic than cisplatin against a variety of tumor cells lines, and induces cell cycle arrest in S-phase and G2-phase. Titanocene dichloride and budotitane were the first anticancer metal complexes to enter clinical trials after platinum compounds [49]. Both complexes bear two labile ligands and hydrolyze quickly in water. However, the nature of their active species and the mechanism of action remained unresolved. Therefore, current studies focus on watersoluble but stable TiIV antitumor complexes [50]. Glasner et al. reported a series of C1 symmetrical TiIVSalan complexes of differently substituted aromatic rings such as 44 and 45 [51]. These hybrid complexes are highly stable and possess much higher anticancer activity than C2 symmetrical TiIV-Salan analogues (46–48) and cisplatin. An additional related advantage of the hybrid complexes is their enhanced solubility in DMSO, which is of interest to therapeutic applications. These complexes, upon hydrolysis, may form different polynuclear salan bound complexes which could be stabilized by nanoparticles [52]. This example illustrated how to achieve highly cytotoxic TiIV complexes by fine-tuning structural parameters of the ligand. The same group has extended their study to trans-TiIV complexes consisting of salophen ligand (Figure 4k) [53]. Again, these www.sciencedirect.com
Metal-based anticancer chemotherapeutic agents Muhammad and Guo 151
complexes exhibited high hydrolytic stability and high cytotoxicity against different carcinoma cells. The structural parameters of the ligand play a crucial role toward the cytotoxicity of the complexes. For example, complex 50 which consist of a para substituted chlorine were found to be much more active than complex 51 which consist of an ortho substituted chlorine.
2.
Guo Z, Sadler PJ: Medicinal inorganic chemistry. Adv Inorg Chem 1999, 49:183-306.
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Kelland L: The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 2007, 7:573-584.
4.
Wang X, Guo Z: Targeting and delivery of platinum-based anticancer drugs. Chem Soc Rev 2013, 42:202-224.
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Butler JS, Sadler PJ: Targeted delivery of platinum-based anticancer complexes. Curr Opin Chem Biol 2013, 17:175-188.
Conclusions
6.
There are growing interests in designing metal-based anticancer agents which are capable of overcoming the problems of clinically used drugs while maintaining their efficacy. PtIV prodrugs are often less toxic than their PtII counterparts, and offer many possibilities for rational design at both axial and equatorial positions. The redox potential, kinetic stability, hydrophilicity/lipophilicity of the PtIV species can be finely tuned by varying the ligands or the substituents of the ligands. Photosensitive PtIV complexes can be selectively activated at tumor tissues to reduce potential damage to healthy ones. Targeting or imaging property can be achieved by conjugating the proper groups to PtIV center. Multinuclear PtII complexes are capable of forming long range DNA cross-linking adducts and possess different mechanism of action from cisplatin. The bridging ligands may play major roles in controlling the reactivity of the PtII centers to S-containing nucleophiles such as GSH. It seems that NAMI-A will not go further for clinical investigations, but this will not discount the potential for ruthenium-based antitumor complexes which will be particularly valuable for their anti-metastatic properties and their potential to overcome cisplatin induced resistances. A broad variety of goldI and goldIII complexes have been shown promising antitumor effects under in vitro and in vivo investigations. The inhibition of TrxR and triggering of antimitochondrial effects appear to be the common mechanism shared by many active gold antitumor agents, although other targets such as DNA and deubiquitinases can be also important. Studies on AuIII compounds concentrate on their stabilization by employing chelating ligands such as polypyridines or dithiocarbamates. Similarly, hydrolytically stable TiIV complexes demonstrated anti-cancer potential.
Acknowledgements We thank the National Basic Research Program of China (no. 2011CB935800) and National Natural Science Foundation of China (nos. 21271100, 91213305, 10979019, 21131003, and 21021062) for financial support.
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10. Kozubik A, Horvath V, Svihalkova-Sindlerova L, Soucek K, Hofmanova J, Sova P, Kroutil A, Zak F, Mistr A, Turanek J: High effectiveness of platinum(IV) complex with adamantylamine in overcoming resistance to cisplatin and suppressing proliferation of ovarian cancer cells in vitro. Biochem Pharmacol 2005, 69:373-383. 11. Wilson JJ, Lippard SJ: Synthesis, characterization, and cytotoxicity of platinum(IV) carbamate complexes. Inorg Chem 2011, 50:3103-3115. A series of platinum(IV) complexes having the general formula cis,cis,trans-[Pt(NH3)2Cl2(O2CNHR)2] were synthesized and shown high cytotoxicity against selected tumor cell lines, and the adiabatic electron affinities of the complexes are correlated with their reduction potentials. 12. Medrano MA, Alvarez-Valdes A, Perles J, Lloret-Fillol J, MunozGalvan S, Carnero A, Navarro-Ranninger C, Quiroga AG: Oxidation of anticancer Pt(II) complexes with monodentate phosphane ligands: towards stable but active Pt(IV) prodrugs. Chem Commun (Camb) 2013, 49:4806-4808. 13. Varbanov HP, Valiahdi SM, Kowol CR, Jakupec MA, Galanski M, Keppler BK: Novel tetracarboxylatoplatinum(IV) complexes as carboplatin prodrugs. Dalton Trans 2012, 41:14404-14415. Investigations on the cytotoxic activity, lipophilicity, electrochemistry and the rate of reduction of tetracarboxylatoplatinum(IV) complexes were carried out to reveal their structure–activity relationship in comparsion with cisplatin prodrugs. 14. Ravera M, Gabano E, Zanellato I, Bonarrigo I, Escribano E, Moreno V, Font-Bardia M, Calvet T, Osella D: Synthesis, characterization and antiproliferative activity on mesothelioma cell lines of bis(carboxylato)platinum(IV) complexes based on picoplatin. Dalton Trans 2012, 41:3313-3320. 15. Pichler V, Goschl S, Meier SM, Roller A, Jakupec MA, Galanski M, Keppler BK: Bulky N(,N)-(di)alkylethane-1,2diamineplatinum(II) compounds as precursors for generating unsymmetrically substituted platinum(IV) complexes. Inorg Chem 2013, 52:8151-8162. Varying the substituents of diamine ligands provide examples of antitumor active Pt(IV) complexes with diverse spectrum of activities. The cytotoxicity of the complexes was interpreted in the context of steric effect of the diamine ligands, and the lipophilicity and redox potential of the complexes. 16. Farrer NJ, Woods JA, Salassa L, Zhao Y, Robinson KS, Clarkson G, Mackay FS, Sadler PJ: A potent trans-diimine platinum anticancer complex photoactivated by visible light. Angew Chem Int Ed 2010, 49:8905-8908. 17. Song Y, Suntharalingam K, Yeung JS, Royzen M, Lippard SJ: Synthesis and characterization of Pt(IV) fluorescein conjugates to investigate Pt(IV) intracellular transformations. Bioconjugate Chem 2013, 24:1733-1740. Current Opinion in Chemical Biology 2014, 19:144–153
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Fluorescent Pt(IV) prodrugs of cisplatin can be turned on by reduction and loss of fluorescent axial ligands, which can be applied for intracellular studies by fluorescence microscopic method. 18. Aryal S, Hu C-MJ, Zhang L: Polymer cisplatin conjugate nanoparticles for acid-responsive drug delivery. ACS Nano 2010, 4:251-258.
cytotoxic ruthenium(III) complexes with bulky triazolopyrimidine ligands. Dalton Trans 2013, 42:6219-6226.
19. Kolishetti N, Dhar S, Valencia PM, Lind LQ, Karnik R, Lippard SJ, Langer R, Farokhzad OC: Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy. PNAS 2010, 107:17939-17944.
34. Pierroz V, Joshi T, Leonidova A, Mari C, Schur J, Ott I, Spiccia L, Ferrari S, Gasser G: Molecular and cellular characterization of the biological effects of ruthenium(II) complexes incorporating 2-pyridyl-2-pyrimidine-4-carboxylic acid. J Am Chem Soc 2012, 134:20376-20387. Coordinatively saturated and substitutionally inert polypyridyl Ru(II) compounds can be potential anticancer drug candidates by targeting the mitochondria of cancer cells.
20. Xiao H, Song H, Yang Q, Cai H, Qi R, Yan L, Liu S, Zheng Y, Huang Y, Liu T et al.: A prodrug strategy to deliver cisplatin(IV) and paclitaxel in nanomicelles to improve efficacy and tolerance. Biomaterials 2012, 33:6507-6519.
35. Li L, Wong YS, Chen T, Fan C, Zheng W: Ruthenium complexes containing bis-benzimidazole derivatives as a new class of apoptosis inducers. Dalton Trans 2012, 41:1138-1141.
21. Graf N, Bielenberg DR, Kolishetti N, Muus C, Banyard J, Farokhzad OC, Lippard SJ: aVb3 integrin-targeted PLGA-PEG nanoparticles for enhanced anti-tumor efficacy of a Pt(IV) prodrug. ACS Nano 2012, 6:4530-4539.
36. Qian C, Wang JQ, Song CL, Wang LL, Ji LN, Chao H: The induction of mitochondria-mediated apoptosis in cancer cells by ruthenium(II) asymmetric complexes. Metallomics 2013, 5:844-854. Ruthenium(II) asymmetric complexes with the lipophilic ancillary ligands derived from 1,10-phenanthroline can induce mitochondria-mediated apoptosis, and the lipophilicity of complexes can be correlated to their cellular uptake and cytotoxic potency.
22. Wedlock LE, Kilburn MR, Liu R, Shaw JA, Berners-Price SJ, Farrell NP: NanoSIMS multi-element imaging reveals internalisation and nucleolar targeting for a highly-charged polynuclear platinum compound. Chem Commun (Camb) 2013, 49:6944-6946. 23. Manzotti C, Pratesi G, Menta E, Di Domenico R, Cavalletti E, Fiebig HH, Kelland LR, Farrell N, Polizzi D, Supino R et al.: BBR 3464: a novel triplatinum complex, exhibiting a preclinical profile of antitumor efficacy different from cisplatin. Clin Cancer Res 2000, 6:2626-2634. 24. Zhao Y, He W, Shi P, Zhu J, Qiu L, Lin L, Guo Z: A positively charged trinuclear 3N-chelated monofunctional platinum complex with high DNA affinity and potent cytotoxicity. Dalton Trans 2006:2617-2619. 25. Wang Y, Wang X, Wang J, Zhao Y, He W, Guo Z: Noncovalent interactions between a trinuclear monofunctional platinum complex and human serum albumin. Inorg Chem 2011, 50:12661-12668. 26. Olivova R, Kasparkova J, Vrana O, Vojtiskova M, Suchankova T, Novakova O, He W, Guo Z, Brabec V: Unique DNA binding mode of antitumor trinuclear tridentate platinum(II) compound. Mol Pharm 2011, 8:2368-2378. 27. Zerzankova L, Kostrhunova H, Vojtiskova M, Novakova O, Suchankova T, Lin M, Guo Z, Kasparkova J, Brabec V: Mechanistic insights into antitumor effects of new dinuclear cis Pt(II) complexes containing aromatic linkers. Biochem Pharmacol 2010, 80:344-351. 28. Lin M, Wang X, Zhu J, Fan D, Zhang Y, Zhang J, Guo Z: Cellular and biomolecular responses of human ovarian cancer cells to cytostatic dinuclear platinum(II) complexes. Apoptosis 2011, 16:288-300. 29. Komeda S, Lin YL, Chikuma M: A tetrazolato-bridged dinuclear platinum(II) complex exhibits markedly high in vivo antitumor activity against pancreatic cancer. ChemMedChem 2011, 6:987-990. 30. Komeda S, Takayama H, Suzuki T, Odani A, Yamori T, Chikuma M: Synthesis of antitumor azolato-bridged dinuclear platinum(II) complexes with in vivo antitumor efficacy and unique in vitro cytotoxicity profiles. Metallomics 2013, 5:461-468. Modification at C5 position of the tetrazole ligand gives rise dinulcear Pt(II) complexes with very different in vitro and in vivo activity which was compared with that of their prototype complexes. 31. Brown SD, Trotter KD, Sutcliffe OB, Plumb JA, Waddell B, Briggs NE, Wheate NJ: Combining aspects of the platinum anticancer drugs picoplatin and BBR3464 to synthesize a new family of sterically hindered dinuclear complexes; their synthesis, binding kinetics and cytotoxicity. Dalton Trans 2012, 41:11330-11339. 32. Sava G, Bergamo A, Dyson PJ: Metal-based antitumour drugs in the post-genomic era: what comes next? Dalton Trans 2011, 40:9069-9075. 33. Lakomska I, Fandzloch M, Muziol T, Lis T, Jezierska J: Synthesis, characterization and antitumor properties of two highly Current Opinion in Chemical Biology 2014, 19:144–153
37. Ang WH, Casini A, Sava G, Dyson PJ: Organometallic ruthenium-based antitumor compounds with novel modes of action. J Organomet Chem 2011, 696:989-998. 38. Suss-Fink G: Arene ruthenium complexes as anticancer agents. Dalton Trans 2010, 39:1673-1688. 39. Kilpin KJ, Cammack SM, Clavel CM, Dyson PJ: Ruthenium(II) arene PTA (RAPTA) complexes: impact of enantiomerically pure chiral ligands. Dalton Trans 2013, 42:2008-2014. 40. Khan F-A, Therrien B, Su¨ss-Fink G, Zava O, Dyson PJ: Arene ruthenium dichloro complexes containing isonicotinic ester ligands: synthesis, molecular structure and cytotoxicity. J Organomet Chem 2013, 730:49-56. 41. Romero-Canelon I, Salassa L, Sadler PJ: The contrasting activity of iodido versus chlorido ruthenium and osmium arene azoand imino-pyridine anticancer complexes: control of cell selectivity, cross-resistance, p53 dependence, and apoptosis pathway. J Med Chem 2013, 56:1291-1300. Organometallic half-sandwich complexes exhibit potent antiproliferative activity toward a range of cancer cells. The iodido complexes were found more potent than the chlorido analogues, which are not cross-resistant with cisplatin and oxaliplatin and more selective for cancer cells versus normal cells. 42. Barry NP, Sadler PJ: Dicarba-closo-dodecarborane-containing half-sandwich complexes of ruthenium, osmium, rhodium and iridium: biological relevance and synthetic strategies. Chem Soc Rev 2012, 41:3264-3279. 43. Ott I: On the medicinal chemistry of gold complexes as anticancer drugs. Coord Chem Rev 2009, 253:1670-1681. 44. Bindoli A, Rigobello MP, Scutari G, Gabbiani C, Casini A, Messori L: Thioredoxin reductase: a target for gold compounds acting as potential anticancer drugs. Coord Chem Rev 2009, 253:1692-1707. 45. Serratrice M, Edafe F, Mendes F, Scopelliti R, Zakeeruddin SM, Gratzel M, Santos I, Cinellu MA, Casini A: Cytotoxic gold compounds: synthesis, biological characterization and investigation of their inhibition properties of the zinc finger protein PARP-1. Dalton Trans 2012, 41:3287-3293. 46. Zou T, Lum CT, Chui SS, Che CM: Gold(III) complexes containing N-heterocyclic carbene ligands: thiol ‘‘switch-on’’ fluorescent probes and anti-cancer agents. Angew Chem Int Ed 2013, 52:2930-2933. Cationic Au(III)–carbene complexes, which demonstrate potent in vivo activity against HeLa xenografts, can also serve as a switch-on probe for biological thiols 47. Ronconi L, Fregona D: The Midas touch in cancer chemotherapy: from platinum- to gold-dithiocarbamato complexes. Dalton Trans 2009:10670-10680. www.sciencedirect.com
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Salan titanium(IV) complexes of aromatic rings halogenated on one ring and nitrated on the other demonstrate high anticancer activity, which combine high activity and stability with improved solubility.
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Current Opinion in Chemical Biology 2014, 19:144–153
ScienceDirect Metal-based anticancer chemotherapeutic agents Nafees Muhammad and Zijian Guo Since the discovery of the cisplatin antitumor activity, great efforts have focused on the rational design of metal-based anticancer agents that can be potentially used in cancer chemotherapy. Over the last four decades, a large number of metal complexes have been extensively investigated and evaluated in vitro and in vivo, and some of them were at different stages of clinical studies. Amongst these complexes, platinum (PtII and PtIV), ruthenium (RuII and RuIII), gold (AuI and AuIII) and titanium (TiIV) complexes are the most studied metals. We describe here some most recent progresses on PtIV prodrugs which can be activated once enter tumor cells, polynuclear PtII complexes which have unique DNA binding ability and mode, anti-metastatic RuII/RuIII complexes, and AuI/AuIII and TiIV antitumor active complexes. The key focuses of these studies lie in finding novel metal complexes which could potentially overcome the hurdles of current clinical drugs including toxicity, resistance and other pharmacological deficiencies. Addresses State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China Corresponding author: Guo, Zijian ([email protected]) Current Opinion in Chemical Biology 2014, 19:144–153 This review comes from a themed issue on Bioinorganic chemistry Edited by Elizabeth M Nolan and Mitsuhiko Shionoya
1367-5931/$ – see front matter, # 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cbpa.2014.02.003
Introduction The modern use of transition metal complexes as chemotherapeutic agents dates back to the serendipitous discovery of cisplatin by Rosenberg et al. in 1965 [1]. Such a discovery opened the gate of unexplored world of metal-based chemotherapeutic agents which have different kinetics and mechanism of action from those of conventional organic drugs [2]. Cisplatin, carboplatin and oxaliplatin are FDA approved platinum anticancer drugs that are used in clinic world-wide for the treatment of various cancers, while nedaplatin, lobaplatin, and heptaplatin are approved for clinical use respectively in Japan, China and Korea (Figure 1). However, side effects, toxicity and drug resistance are the major obstacles for wider clinical application of these drugs [3]. Bioinorganic and medicinal chemists are exploring different strategies to overcome the problems, which Current Opinion in Chemical Biology 2014, 19:144–153
includes targeted delivery of clinical drugs [4,5] and design of novel platinum and non-platinum metal complexes which have different structural features and reactivities [6]. Because of the excellent review coverage on the chemistry, biology and medicine of PtII-based anticancer drugs, in this short review we concentrate on some most recent advances on PtIV prodrugs, polynuclear PtII complexes, and RuII/III, AuI/III and TiIV-based anticancer complexes.
Pt(IV) prodrugs: a strategy to reduced toxicity and drug resistance PtIV complexes came into the medicinal stage soon after the toxicity of cisplatin became a major clinical issue for cancer treatment. It is believed that octahedral PtIV complexes are kinetically more inert in blood stream but can be activated once enters into the cells by reducing agents to give cytotoxic PtII species, offering potential advantage over PtII compounds regarding oral availability, reduced drug resistance and toxicity. Following the early efforts of Rosenberg and co-workers on PtIV analogues of cisplatin [7], thousands of PtIV complexes have been synthesized and evaluated in the context of prodrugs. The rationales behind the design of PtIV complexes are the fine tuning of their redox potential, kinetic stability, hydrophilicity/lipophilicity to achieve desired reactivity and activity through selection of axial and equatorial ligands. Two best known examples are satraplatin (1) (formally known as JM216) and LA-12 (2) [8]. Satraplatin 1 was once in the advanced stage of clinical trials for prostate, lung and ovarian cancers. It can be orally active, unlike other PtII drugs which have to be given intravenously. As a prodrug, 1 is activated by reduction in the presence of intracellular reducing agents such as glutathione, ascorbic acid, among others [9], and demonstrates little nephrotoxicity, neurotoxicity and ototoxicity. Complex 2 is an analogue of 1 and contains a bulky hydrophobic ligand, adamantylamine which could potentially increase the uptake of 2 by the cancer cells. Complex 2 was significantly more efficient than cisplatin against cisplatin resistant ovarian carcinoma A2780cisR cells, causing the increase of p53 level and cell cycle perturbations [10]. Wilson et al. synthesized a series of PtIV carbamate complexes (3–5) by reacting various alkyl and aryl isocyanates with PtIV hydroxy complex [Pt(NH3)2Cl2(OH)2] [11]. Slightly higher reduction potentials were found for the aryl carbamate complexes than for the alkyl carbamate complexes, which can be correlated with computed adiabatic electron affinities. All these complexes show equivalent or higher cytotoxicity than cisplatin against human www.sciencedirect.com
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Figure 1
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Clinically approved PtII drugs and complexes evaluated in clinical trials.
lung carcinoma A549 cells. In addition, compounds 4 and 5 that contain tert-butyl and cyclopentyl based carbamate ligands showed higher cytotoxicity than other complexes of this series. It is worth to mention that these complexes show higher cytotoxicity against cancer cells than normal cells such as normal lung MRC-5 cells. Medrano et al. [12] have synthesized two trans-PtIV phosphane complexes 6 and 7 to take advantage of the lipophilicity of phosphane group. Both complexes contain aliphatic amines trans to phosphane ligands, which enhances the stability of PtIV complexes. Both 6 and 7 are stable in solution and have IC50 values similar to that of cisplatin against carcinoma cell lines NCI-H460 and metastatic melanoma A375. Interestingly, both complexes were shown to be more selective and cytotoxic than that of cisplatin against HCT116 cells absent of wildtype p53 (HCT116 / cells). By tethering lipophilic carboxylate ligands in the axial position, Varbanov et al. have prepared a series tetracarboxylate PtIV complexes which demonstrate potent cytotoxicity against a variety of cancer cell lines (8, Figure 2e) [13]. It was concluded that both the reduction potential and the rate of reduction has major influences on the cytotoxic properties of these complexes and their amide/ ester derivatives. Another series of dicarboxylated PtIV complexes 10–12, which were developed by Ravera et al. [14], were based on picoplatin (Figure 1), an active PtII antitumor agent able to circumvent acquired Pt-chemotherapy resistance. The presence of a sterically demanding 2-methylpyridine in picoplatin hinders the www.sciencedirect.com
axial approach of GSH to the platinum center without detriment of the level of DNA platination. These complexes demonstrated potent activity against several different tumor cell lines sensitive and resistant to cisplatin. Interestingly, the cytotoxicity and selectivity of these complexes against resistant cell lines increases with the elongation of the axial chain. Pichler et al. [15] have recently synthesized a series of symmetrically and unsymmetrically substituted PtIV complexes containing various bulky groups at the equatorial position (e.g. 13–15). These bulky groups were found to play a major role in determining the stability and reaction patterns of the PtIV complexes. All these complexes show strong inhibitory effect against different tumor cell lines sensitive and resistant to cisplatin. An interesting correlation between the cytotoxicity and the lipophilicity of the complexes was proposed, although it is neither strong nor strictly linear, and has some exceptions. Selective photoactivation of PtIV complexes in cancer cells might avoid toxic side effects and extend their application to cisplatin resistant cells. Farrer et al. [16] reported a trans di-pyridine complex 16 which can be phototoxic against a number of human carcinoma cells when irradiated with UVA and visible light. This diazido complex is stable in solution and particularly inert toward GSH. The pyridine ligands appear to remain strongly bound to platinum, even after photoactivation. It seems clear that the molecular pharmacology of the photoactivatable excited state PtIV complex 16 is quite distinct from that of ground-state PtIV complexes. Current Opinion in Chemical Biology 2014, 19:144–153
146 Bioinorganic chemistry
Figure 2
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PtIV prodrugs. (a) Orally bioavailable satraplatin or JM216 (1). (b) LA-12, an analogue of satraplatin (2). (c) PtIV carbamate complexes (4 and 5). (d) trans-PtIV phosphane complexes (6 and 7). (e) Tetracarboxylate PtIV complex (8). (f) Picoplatin based dicarboxylated PtIV Complexes (10–12). (g) PtIV complexes with various bulky groups at the equatorial position (13–15). (h) Photoactivated trans di-pyridine PtIV complex (16). (i) Fluorescently labeled PtIV compound (17). (j) Acid responsive polymer drug conjugate, where n = 400–450 (18). (k) Targeted delivery of PtIV prodrug through RGD modified delivery vehicle.
Fluorescently labeled PtIV compounds can be potentially used in live cell imaging to monitor PtIV reduction. Song et al. [17] designed fluorescent PtIV prodrugs such as 17 by tethering fluorescein-derived ligands at the axial Current Opinion in Chemical Biology 2014, 19:144–153
position of dihydroxido PtIV precursors. The fluorescence of the ligands is quenched when bound to PtIV center. However, the reduction of 17 by biological reductants such as GSH or ascorbate results in the release of www.sciencedirect.com
Metal-based anticancer chemotherapeutic agents Muhammad and Guo 147
fluorescent ligands which consequently restores their fluorescence. These complexes can be potentially utilized to study intracellular reduction of PtIV prodrugs. The development of nano-carriers and nano-vehicles has recently gained very much attention for safer and targeted delivery of anticancer drugs [4,5]. The two axial positions in PtIV prodrugs offer great synthetic flexibility for further chemical modification and conjugation with nanomaterials. As a consequence, the therapeutic efficacy of PtIV prodrugs can be improved. For example, Aryal et al. have synthesized acid responsive polymer nanoparticles consisting of covalently linked polymer PtIV conjugate 18 (Figure 2j) [18]. The presence of hydrazone bond in 18 gives a highly differential drug release profile at different environmental acidity. During nanoparticle circulation in the blood, where the pH value is neutral, 18 is stable. However, upon its endocytosis by the target cells, where the pH value is acidic, rapid intracellular drug release is triggered. Kolishetti et al. [19] have synthesized selfassembled aptamer conjugated PLA nanoparticles for targeted delivery or co-delivery of cisplatin, PtIV prodrug and docetaxel to the prostate cancer cells. Similarly, Xiao et al. [20] reported a composite micelles containing both PtIV prodrug and paclitaxel. A synergetic effect of two therapeutic drugs was observed at both in vitro and in vivo experiments. A polymeric NP system comprising an encapsulated PtIV prodrug and cyclic RGD peptides (Figure 2k) as integrin targeting moieties has been developed for anticancer therapy [21].
Multinuclear platinum(II) complexes: unique DNA binding mode and ability Polynuclear PtII complexes represent a new class of anticancer agents that possess potent and distinct biological activity from cisplatin [22]. One of the most successful compounds is BBR3464 (Figure 1) which was once in Phase II clinical trials for the treatment of patients with melanoma, pancreatic, lung, ovarian and gastric tumors [23]. The complex is composed of two monofunctional Pt moieties, and the two separated Pt–Cl bonds maintain the bifunctional binding mode on DNA and form long range cross-linking adducts. Multinuclear PtII complexes offer different reactivities and biological activities from those of cisplatin and its analogues. Cytotoxic trinuclear complex 19 (Figure 3a) contains three monofunctional Pt–Cl motifs bridged by a bis(pyridylmethyl)amine ligand [24]. It demonstrated unique binding features to protein and DNA. For example, it interacts with human serum albumin at the hydrophobic cavity of domain II mainly through non-covalent actions [25]; it binds to DNA forming unique trifunctional intrastrand cross-linking adducts [26]. When two cisplatin moieties were bridged by aromatic linkers of different length, cytotoxic complexes 20 and 21 were obtained. Both complexes form preferentially inter-strand DNA www.sciencedirect.com
cross-linking adducts which can be recognized and bound strongly by high-mobility-group-domain proteins [27]. These complexes induce some cellular responses different from those caused by cisplatin. For example, they arrest the cell cycle in G2 or M phase, while cisplatin arrests the cell cycle in S phase; there are evidences that their cytostatic activity is closely associated with the activation of signaling pathways such as phosphoERK1/2 and phospho-p38 MAPK [28]. Komeda et al. have developed dinuclear PtII complexes using tetraazolate as a bridging ligand [29]. Complex 22 was formed at higher ratio than its isomer 23 probably due to the higher nucleophilicity of N1 or N4 bound to one C and one N atom, compared with N2 or N3 bound to two N in tetraazolate ligand. These complexes demonstrated potent activity against selected tumor cell lines and xenografts. The same group has extended their study to complexes with tetrazole ligands modified at C5 position (Figure 3d). Cytoxicity screening illustrates that the tailoring groups have an important impact on their activity. Among them 27 showed remarkable antitumor efficacy against pancreatic PANC-1 xenograft in nude mice [30]. These complexes offered a diverse skeleton for the design of novel antitumor complexes. Brown et al. reported a series of sterically hindered dinuclear PtII complexes such as complex 29 with bispyridyl based ligands containing diaminoalkanes of different lengths [31]. It is hypothesized that these complexes could combine the advantages of picoplatin (inert to sulfur nucleophiles) and BBR3464 (long range DNA cross-links). The cytotoxicity of these complexes was evaluated against human ovarian carcinoma A2780 cells and its cisplatin resistant cell lines. This work provides a proof-of-concept for the development of a larger family of sterically hindered multinuclear-based platinum complexes.
Ruthenium anticancer complexes: antitumor metastasis and overcome cisplatin resistance Ruthenium has several oxidation states (RuII, RuIII and RuIV) which can be tunable under physiological conditions. Ruthenium complexes have the same kinetic spectrum of ligand substitution as that of PtII complexes in aqueous medium, therefore are suitable alternative to PtII anticancer drugs. In the past few decades, several ruthenium (RuII and RuIII) complexes were developed and studied for their antiproliferative activities against various tumor models, but a real breakthrough comes from the development of NAMI-A (30) and KP1019 (31) (Figure 4a) ruthenium compounds which are now under clinical trials. These complexes are particularly useful for the treatment of metastatic tumors or cisplatin resistant tumors. Both of these complexes are structurally similar to each other but having a different cytotoxic profile toward the tumor cells. For example, 30 shows Current Opinion in Chemical Biology 2014, 19:144–153
148 Bioinorganic chemistry
Figure 3
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Multinuclear platinum complexes. (a) Trinuclear PtII complex containing three monofunctional Pt-Cl motifs (19). (b) Dinuclear PtII complexes connected by aromatic linkers (20 and 21). (C) Dinuclear PtII complexes with tetraazolate as bridging ligand (22 and 23). (d) Dinuclear PtII complexes with tetrazole ligands modified at C5 position (25–28). (e) Dinuclear PtII complex with bis-pyridyl based ligands (29).
little activity against primary tumors but found to be highly active against secondary tumors such as non-small cell lung cancer and inhibits the lung metastases, while KP1019 (31) shows potent cytotoxicity against primary tumors especially in colorectal cancer which is resistant to cisplatin chemotherapy. It should be noted that both complexes are only moderately active in vitro but is better tolerated in vivo and in clinical applications [32]. Solubility, tumor targeting and absorption are major issues concerned in the design of novel ruthenium complexes. Lakomska et al. have developed two RuIII complexes (Figure 4b) based on triazolopyrimidine ligands [33]. By introducing bulky substituents in the heterocyclic Current Opinion in Chemical Biology 2014, 19:144–153
ligands, the cytotoxicity of both complexes is significantly enhanced. For example, 32 and 33 show much higher cytotoxicity than that of cisplatin against human lung carcinoma A-549 and T47D breast carcinoma cell lines with IC50 values in the range of 0.02–2.4 mM range. The authors correlated the high cytotoxicity of these complexes to their high lipophilicity which is generally believed to facilitate cellular uptake. Pierroz et al. have synthesized a series of RuII polypyridyl complexes which are coordinatively saturated and substitutionally inert [34]. Among these complexes, 34 was found to have IC50 values comparable to cisplatin against several different cancer cell lines and better activity www.sciencedirect.com
Metal-based anticancer chemotherapeutic agents Muhammad and Guo 149
Figure 4
(b)
(a)
(30) (31) (c)
(32)
(33) (e)
(d)
(35) = Phen (36) (34) (g)
(f)
(h)
(38) (37)
(39) (j)
(i)
(43)
(40)
(41)
(k)
44 L1,2. R= p-NO2, R’= o,p-Cl 45 L1,3. R= p-NO2, R’= o,p-Br 46 L1,1. R=R’= p-NO2 47 L2,2. R=R’= p-Cl 48 L3,3. R=R’= o,p-Br
(42) 50 R= 4-Cl 51 R= 2-Cl (49) Current Opinion in Chemical Biology
Ruthenium, gold and titanium based anticancer complexes. (a) Ruthenium based drugs in clinical trials NAMI A (30) and KP1019 (31). (b) RuIII complexes based on triazolopyrimidine ligands (32 and 33). (c) RuII polypyridyl complex (34). (d) RuII complex comprises of mixed ligand (35). (e) Mitochondrial targeted mixed ligand based RuII complex (36). (f) RuII-arene complexes (37). (g) AuI/AuIII complexes with imidazolate derivatives (38–40). (h) AuIII complexes with N-heterocyclic carbene ligands (41 and 42). (i) AuIII-dithiocarbamate complex (43). (j) Symmetrical TiIV-Salan complexes (44–48). (k) Trans-TiIV complexes consisting of salophen ligand (50 and 51).
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150 Bioinorganic chemistry
against cisplatin-resistant cell line than cisplatin. Complex 34 was found to target the mitochondria of cancer cells and induce mitochondrial mediated apoptosis. Interestingly, subtle structural changes can have a significant impact on both the cytotoxicity and cellular localization of this series of complexes. When the 4-carboxylic acid group in 34 was replaced by a hexanoic acid group, the RuII complex loses the cytotoxicity and targeting property. Li et al. synthesized a series of RuII complexes containing bis-benzimidazole derivatives, and introduced phenathroline as a mixed ligand for comparison [35]. These complexes were screened against a series of tumor cell lines and a normal human fibroblast (HS68) cell line. Among them, complex 35 shows selective cytotoxicity against tumor cell lines but very little toxicity against Hs68 normal cells. It induces caspase-dependent apoptosis in cancer cells through overproduction of superoxide. Qian et al. revealed that mixed ligand RuII complexes such as 36 exhibit potent activity against a variety of tumor cell lines [36]. Complex 36 accumulates preferentially in the mitochondria of HeLa cells and induces apoptosis via the mitochondrial pathway, which involved ROS generation, mitochondrial membrane potential depolarization, and Bcl-2 and caspase family member activation. Sadler, Dyson and others have developed a series of RuIIarene based antitumor active complexes [37,38]. These organometallic complexes are remarkably stable in biological media and can be recognized by various biotargets. They often have amphiphilic properties and are very active against a variety of tumor models [39,40,41]. RuII-arene system (37) offers a rich platform for incorporation of a variety of functional groups at either the metal center or arene moiety [42].
Gold and titanium anticancer complexes: multiple targets In the last few decades, many AuI and AuIII compounds with different molecular structures have been developed and tested as anticancer agents. Gold complexes with phosphine and carbene ligands, dithiocarbamates, porphyrinates have been among the most widely investigated in vitro and in vivo [43]. Although the molecular mechanism of action remains to be elucidated, some relevant biochemical properties of gold complexes are shared in common. For example, the inhibition of thioredoxin reductase (TrxR), DNA and protein binding, the triggering of antimitochondrial effects and the induction of apoptotic events, among others have been confirmed for different gold compounds, which contributes to their pharmacological profiles [44]. Serratrice et al. reported a series of AuI/AuIII complexes with imidazolate derivatives such as 38, 39 and 40 (Figure 4g) [45]. These complexes were evaluated against Current Opinion in Chemical Biology 2014, 19:144–153
ovarian and breast carcinoma cell lines, and the AuI dinuclear complexes 39 and 40 showed higher cytotoxicity than cisplatin. Notably, most of the tested AuI/AuIII complexes demonstrated higher cytotoxicity than cisplatin against cisplatin resistance ovarian cancer cells, which indicates a different mechanism of action for gold complexes. Zou et al. reported a series of AuIII complexes with Nheterocyclic carbene Ligands [46]. These complexes can be used as both thiol ‘‘switch-on’’ fluorescent probes and anti-cancer agents. For example, when AuIII in complex 41 is reduced to AuI by biological thiols such as glutathione or cysteine fluorescent ligand is released, which gives a 200-fold emission enhancement. Complex 42 demonstrated highest in vitro cytotoxicity among the tested complexes, therefore it was further evaluated in vivo using nude mice bearing HeLa xenografts. Significant reduction in tumor volume was observed. Ronconi et al. have proved that AuIII-dithiocarbamate complexes can be promising anticancer agents owing to their interesting in vitro and in vivo cytotoxic activity combined with negligible toxic side-effects [47]. Deubiquitinases, a family of proteases that regulate the ubiquitin system by specifically hydrolyzing isopeptide or peptide bonds between ubiquitin and its conjugated proteins, can be potential target for organometallic AuIII-dithiocarbamate complexes [48]. For example, complex 43 showed 55% inhibition of deubiquitinases in breast carcinoma MCF7 cells in a time dependent manner. It is more cytotoxic than cisplatin against a variety of tumor cells lines, and induces cell cycle arrest in S-phase and G2-phase. Titanocene dichloride and budotitane were the first anticancer metal complexes to enter clinical trials after platinum compounds [49]. Both complexes bear two labile ligands and hydrolyze quickly in water. However, the nature of their active species and the mechanism of action remained unresolved. Therefore, current studies focus on watersoluble but stable TiIV antitumor complexes [50]. Glasner et al. reported a series of C1 symmetrical TiIVSalan complexes of differently substituted aromatic rings such as 44 and 45 [51]. These hybrid complexes are highly stable and possess much higher anticancer activity than C2 symmetrical TiIV-Salan analogues (46–48) and cisplatin. An additional related advantage of the hybrid complexes is their enhanced solubility in DMSO, which is of interest to therapeutic applications. These complexes, upon hydrolysis, may form different polynuclear salan bound complexes which could be stabilized by nanoparticles [52]. This example illustrated how to achieve highly cytotoxic TiIV complexes by fine-tuning structural parameters of the ligand. The same group has extended their study to trans-TiIV complexes consisting of salophen ligand (Figure 4k) [53]. Again, these www.sciencedirect.com
Metal-based anticancer chemotherapeutic agents Muhammad and Guo 151
complexes exhibited high hydrolytic stability and high cytotoxicity against different carcinoma cells. The structural parameters of the ligand play a crucial role toward the cytotoxicity of the complexes. For example, complex 50 which consist of a para substituted chlorine were found to be much more active than complex 51 which consist of an ortho substituted chlorine.
2.
Guo Z, Sadler PJ: Medicinal inorganic chemistry. Adv Inorg Chem 1999, 49:183-306.
3.
Kelland L: The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 2007, 7:573-584.
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Wang X, Guo Z: Targeting and delivery of platinum-based anticancer drugs. Chem Soc Rev 2013, 42:202-224.
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Conclusions
6.
There are growing interests in designing metal-based anticancer agents which are capable of overcoming the problems of clinically used drugs while maintaining their efficacy. PtIV prodrugs are often less toxic than their PtII counterparts, and offer many possibilities for rational design at both axial and equatorial positions. The redox potential, kinetic stability, hydrophilicity/lipophilicity of the PtIV species can be finely tuned by varying the ligands or the substituents of the ligands. Photosensitive PtIV complexes can be selectively activated at tumor tissues to reduce potential damage to healthy ones. Targeting or imaging property can be achieved by conjugating the proper groups to PtIV center. Multinuclear PtII complexes are capable of forming long range DNA cross-linking adducts and possess different mechanism of action from cisplatin. The bridging ligands may play major roles in controlling the reactivity of the PtII centers to S-containing nucleophiles such as GSH. It seems that NAMI-A will not go further for clinical investigations, but this will not discount the potential for ruthenium-based antitumor complexes which will be particularly valuable for their anti-metastatic properties and their potential to overcome cisplatin induced resistances. A broad variety of goldI and goldIII complexes have been shown promising antitumor effects under in vitro and in vivo investigations. The inhibition of TrxR and triggering of antimitochondrial effects appear to be the common mechanism shared by many active gold antitumor agents, although other targets such as DNA and deubiquitinases can be also important. Studies on AuIII compounds concentrate on their stabilization by employing chelating ligands such as polypyridines or dithiocarbamates. Similarly, hydrolytically stable TiIV complexes demonstrated anti-cancer potential.
Acknowledgements We thank the National Basic Research Program of China (no. 2011CB935800) and National Natural Science Foundation of China (nos. 21271100, 91213305, 10979019, 21131003, and 21021062) for financial support.
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