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In this chapter, we have endeavoured to showcase how some clinically approved drugs may be exploited as potential ligands when designing new metallodrugs to treat cancer. Interestingly, while there is a sound rationale behind repurposing existing drugs, those to date that have been tethered to platinum(ii) and platinum(iv) centres have not been chosen for this purpose. Rather, they have been selected because these drugs, in their own right, have exhibited potent anticancer activities albeit some are in clinical use for other indications. This chapter will provide an overview of some interesting platinum(ii) and platinum(iv) complexes incorporating a selection of clinically approved drugs or derivatives thereof as ligands. These complexes may form the basis of a new drug class which may offer advantages over existing therapeutic regimens.

Cancer is a multi-factorial disease which results from a myriad of genetic and environmental factors. It continues to represent a global health challenge not least because the global population is growing and ageing but also because access to information related to its prevention, early detection and treatment options, particularly in developing countries, is limited. The lack of provision of adequate medical and public health infrastructure are also contributory factors.1  While there are different options to treat cancer, they typically include a combination of surgery, chemotherapy and/or radiotherapy. Immunotherapy, a form of treatment which stimulates our immune system to kill cancer cells,2  and oncolytic virotherapies,3  are also emerging as promising options to complement existing therapeutic regimens.

Chemotherapeutic drugs operate either alone or in combination regimens by blocking the unwanted proliferation of cancer cells. Platinum drugs constitute a major chemotherapeutic drug class for the treatment of cancer. In fact, it has been stated that nearly 50% of all cancer treatments involve platinum drugs.4  Despite their clinical success, there are currently only three platinum drugs in worldwide clinical use, namely cisplatin (1), carboplatin (2) and oxaliplatin (3) and three others, nedaplatin (4), heptaplatin (5) and lobaplatin (6) in use in Japan, South Korea and China respectively (see Figure 1.1).5  These square planar platinum(ii) drugs contain ‘non-leaving’ nitrogen donor ligands and labile chlorido or dicarboxylato ligands. Cisplatin, as a representative example, elicits its anticancer effect by first accumulating in tumour cells, whereupon the labile ligands are displaced by water ligands. It is these resulting aquated platinum(ii) species that can then irreversibly bind DNA (typically to the N7 of guanine nucleobases) leading to the formation of DNA lesions and ultimately triggering apoptosis or programmed tumour cell death. The reader is directed to a recent review which provides a comprehensive account into the development, mechanism of action and clinical utility of these ‘classical’ platinum(ii) drugs.5 

Figure 1.1

Platinum drugs in clinical use (16) with the years in which they received regulatory approval indicated in parentheses.

Figure 1.1

Platinum drugs in clinical use (16) with the years in which they received regulatory approval indicated in parentheses.

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It is broadly acknowledged that these drugs are enormously successful against a wide range of cancers. They do however have significant limitations. While the lability of the anionic ‘leaving’ ligands is important for anticancer activity as mentioned earlier, it also means that the complexes are more susceptible to ligand substitution. Cisplatin, for example, can readily react with thiol-containing biomolecules such as glutathione and metallothioneins. These side reactions not only account for the toxicity profile associated with cisplatin and related complexes, from minor to dose-limiting, but also play a role in the emergence of resistance against platinum drugs.6  For example, some cancer cells are known to overexpress thiol-containing biomolecules so even if the platinum drug accumulates successfully in tumour cells, those that contain high concentrations of these thiol-containing biomolecules compete with DNA for platinum drug binding. This leads to a reduction or elimination in the efficacy of the drug towards those cells. Of the platinum drugs in clinical use, all but cisplatin contain bidentate dicarboxylato ligands. These chelating bidentate ‘leaving’ ligands were chosen on the basis that they would confer greater stability on the complexes (chelate effect), enhancing their half-lives and thus reducing their susceptibility to these unwanted side reactions. The more stable carboplatin, for example, is significantly less toxic on the body than cisplatin.5  In addition to limiting the formation of platinum-DNA adducts, cells have also acquired other modes in which to build resistance and reduce drug sensitivity to cancer cells. Such resistance can arise from multiple factors including genetic and epigenetic changes as outlined in a comprehensive review by Gottesman et al.7  The reader is also referred to another relevant review on molecular mechanisms underpinning platinum drug resistance in ovarian cancer by Tapia et al.6 

In order to overcome toxicity and resistance issues associated with these ‘classical’ platinum drugs, a number of research approaches have been and continue to be actively explored. Early research focused on developing analogues of cisplatin, i.e. complexes in the cis configuration containing a central platinum(ii) ion, with ammine or substituted amine non-leaving group(s) and anionic labile ligands but none were found to offer any significant advantage over cisplatin.8 Trans analogues9,10  and polynuclear platinum(ii) drugs11,12  have also been investigated with one trinuclear complex, BBR3464,13  advancing to phase II clinical trials. This trinuclear complex represented the first example of a ‘non-classical’ platinum drug to advance to the clinical setting. This breakthrough undoubtedly prompted scientists working in this field to explore more ‘non-traditional’ approaches in their drug design strategies. There now appears to be a tangible shift in research focus which is resulting in a more ‘targeted’ approach in the quest to bring forward an alternative ‘classical’ or ‘non-classical’ drug class. The exploitation of nanotechnologies to selectively deliver platinum drugs to tumour cells is one such approach, which has received considerable attention of late.5,14,15  An alternative approach is to tether targeting moieties on the platinum(ii) scaffold to generate complexes with greater selectivity for tumour cells and this may reduce unwanted side reactions and thus lower toxic side effects.5  Developing complexes with a mechanism of action different to classical platinum(ii) drugs is another area being actively explored. These complexes may be able to overcome drug resistance issues that have been plaguing many therapeutic regimens including those related to platinum drugs. Alternatively, targeting drug transport mechanisms may lead to new complexes with an improved chemotherapeutic profile.16  Another design strategy is to move from square planar platinum(ii) to the more kinetically inert, octahedral platinum(iv) complexes. Platinum(iv) complexes may offer advantages over platinum(ii) drugs in that the coordinatively saturated platinum(iv) centre is more resistant to ligand substitution. This may prevent the aforementioned unwanted side reactions with biomolecules and may thus increase the safety profile of these drugs. Furthermore, the presence of six coordination sites in octahedral platinum(iv) complexes, as opposed to four in square planar platinum(ii) complexes, allows for greater latitude in terms of adding extra functionality. For example, it is possible to incorporate bioactive ligands or targeting vectors in these axial positions. Upon uptake into the more reducing environment found in tumour cells, the bioactive ligands may be released following reduction of the platinum(iv) complex to its platinum(ii) analogue, a mechanism referred to as ‘activation by reduction’, and these ligands may then work synergistically with the resulting platinum(ii) agent in killing cancer cells.5,17,18 

Furthermore, given the rising costs associated with drug development, in addition to the growing timeframe involved in getting a drug ‘from bench to shelf’, academia and industry are also focusing on ways in which to ‘repurpose’ existing drugs – this could potentially lead to an accelerated route for drug discovery.19  In this context and in this chapter, we have endeavoured to showcase how clinically approved drugs or derivatives thereof may be exploited as potential ligands and how their corresponding platinum(ii) and platinum(iv) complexes may form the basis of a new drug class which may offer advantages over existing therapeutic regimens. Interestingly, while there is a sound rationale behind repurposing existing drugs, those to date that have been tethered to platinum have not been chosen for this purpose. Rather, they have been selected because they, in their own right, have exhibited anticancer activities albeit some are in clinical use for other indications.

Over 47% of approved drugs have been shown to target the inhibition of enzymes.20,21  Enzyme inhibition continues to represent an attractive target when designing new drugs including metal-based anticancer agents.22  Hydroxamic acids constitute an important class of metalloenzyme inhibitors.23,24  For example, Vorinostat (7) and Belinostat (Bel) (8) (see Figure 1.2) are two hydroxamate-based enzyme inhibitors which are used clinically to treat cancer patients. Vorinostat, also known as suberoylanilide hydroxamic acid (SAHA), received FDA approval in 2009 as a treatment for cutaneous T-cell lymphomas in patients with progressive, persistent, or recurrent disease on or following two systemic therapeutic regimes.25–27  It is marketed under the name Zolinza and was developed by Merck. Belinostat (Bel) (8) (Figure 1.2) also referred to as Beleodaq or PDX101, is a second generation analogue of Vorinostat. It was granted FDA approval in 2014 for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma, a rare and fast-growing type of non-Hodgkin lymphoma (NHL).28–30  It was developed by TopoTarget (now Onxeo) and Spectrum Pharmaceuticals.30,31  Both Vorinostat and Bel are currently in various stages of clinical trials for a number of solid malignancies, including ovarian cancer.32 

Figure 1.2

Chemical structures of Vorinostat (7), Belinostat (8), Pt-malSAHA (9)41,45  and Pt-malBel (10).46 

Figure 1.2

Chemical structures of Vorinostat (7), Belinostat (8), Pt-malSAHA (9)41,45  and Pt-malBel (10).46 

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The anticancer effects of Vorinostat and Bel have been primarily attributed to their ability to inhibit a class of enzymes known as histone deacetylases (HDAC). These HDAC enzymes, together with histone acetyltransferases (HAT), play a key role in chromatin organisation. Chromatin is a highly compact, tense structure made up of small, positively charged histone proteins around which the negatively charged DNA coils.33  Acetylation of these core proteins, mediated by HATs, results in relaxation of the chromatin structure, and this upregulates transcription. Deacetylation, in contrast, causes the chromatin structure to condense which in turn downregulates transcription. Disruption of either enzyme-catalysed process alters the structure which then impacts on the function of chromatin.34 

The hydroxamate functional group of Vorinostat and Bel has been shown to play a key role in their ability to inhibit the HDAC enzymatic function. For example, from crystallographic and molecular modelling studies, Vorinostat has been shown to bind directly to the zinc ion at the enzyme active site. The aliphatic six-carbon spacer of Vorinostat fits neatly into a narrow channel within the enzyme structure while the phenyl ring of Vorinostat interacts with the enzyme surface via hydrophobic interactions.35 

At around the same time that Vorinostat was advancing to the clinic as an anticancer agent, we had been trying to generate some novel platinum(ii)-hydroxamato36,37  and ruthenium(iii)-hydroxamato38–40  complexes. We found that the hydroxamic acid ligand did not readily bind to the platinum(ii) centre, rather it required an ancillary metal binding group in order to successfully coordinate to the platinum ion.36  Inspired by the in vitro and in vivo cytotoxicity profile of Vorinostat and its success in clinical trials, we decided to derivatise Vorinostat in such a way as to facilitate its binding to a cisplatin core while not compromising its HDAC inhibition activity. We did this by incorporating a platinum-binding malonate linker on the phenyl ring of Vorinostat while leaving the hydroxamate moiety free to interact with the HDAC active site zinc ion. This resulted in the generation of the first example of a dual threat platinum(ii)-HDAC inhibitor complex, cis-[PtII(NH3)2(malSAHA-2H)] (herein referred to as Pt-malSAHA) (9) (see Figure 1.2).41  The idea was that this Pt-malSAHA complex would combine, into one drug molecule, the DNA-binding properties of the platinum(ii) carboplatin-like scaffold with the HDAC inhibitory properties of Vorinostat. Our design strategy was further motivated by the fact that HDAC inhibitors, including Vorinostat, had been shown to have preferential selectivity for tumour cells over healthy ones.42,43  They were also found to synergistically enhance the anticancer efficacy of existing drugs, including cisplatin.44  This Pt-malSAHA complex was found to bind DNA, inhibit the HDAC8 enzyme (albeit to a lesser extent than Vorinostat) and, significantly, had potent in vitro cytotoxicity against a range of cisplatin-sensitive and cisplatin-resistant tumour cell lines.41,45  Interestingly, the Pt-malSAHA complex was significantly less toxic (by one order of magnitude) compared to cisplatin against a representative healthy normal human dermal fibroblast (NHDF) cell line.41  A more in depth follow-up study provided evidence that the complex accumulated better in tumour cells, much more so than cisplatin or Vorinostat but it bound to DNA less readily when compared to cisplatin.45  In hindsight, this is not surprising given that the chelating malonate linker bound to the platinum ion in Pt-malSAHA would be expected to be considerably less labile than the chlorido ligands of cisplatin. DNA binding was found to be enhanced in the presence of thiol-containing molecules such as glutathione and thiourea, and complex activation occurred in cytosolic but not nuclear extracts of human cancer cells.45 

We likewise derivatised Bel, as we did with Vorinostat, and complexed this malonate-substituted Bel to the square planar PtII(NH3)2 framework to generate cis-[PtII(NH3)2(malBel-2H)] (Pt-malBel) (10) the Bel analogue of Pt-malSAHA (9) (see Figure 1.2).46  While it exhibited cytotoxicity comparable to that of Pt-malSAHA (9) against cisplatin-sensitive A2780 ovarian cells, it was considerably more cytotoxic when compared to Pt-malSAHA against the cisplatin-resistant A2780cisR cells. Like Pt-malSAHA, it too was considerably less toxic against a representative healthy NHDF cell line. These studies provided one of the first examples of how the therapeutic potential of platinum-based anticancer agents, such as cisplatin, could be enhanced by incorporating clinically approved drugs, or derivatives thereof, as ligands. For example, preliminary evidence suggests that the Pt-malSAHA complex, when compared with cisplatin, has the advantage of being significantly less toxic to healthy cells while retaining a cytotoxicity profile similar to that of cisplatin – it may thus overcome some of the dose-limiting toxic side effects associated with cisplatin and therefore be better tolerated by cancer patients, were it to progress to the clinic.

We mentioned previously the advantages of ‘repurposing’ existing drugs as an accelerated route for drug discovery. Valproic acid (VPA, 2-propylpentanoic acid) (11) (Figure 1.3) is one such drug which may fall into this category. It is used clinically to treat epilepsy and bipolar disorder and is included in the World Health Organization's List of Essential Medicines.47 

Figure 1.3

Chemical structures of valproic acid (VPA) (11), platinum(ii)-VPA complexes (12–13),49  platinum(iv)-VPA complexes (14–18)53–55  and a platinum(iv)-octanoate complex (19).

Figure 1.3

Chemical structures of valproic acid (VPA) (11), platinum(ii)-VPA complexes (12–13),49  platinum(iv)-VPA complexes (14–18)53–55  and a platinum(iv)-octanoate complex (19).

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A number of platinum(ii)- and platinum(iv)-VPA complexes have been reported. The stimulation behind their development was not however to ‘repurpose’ VPA but rather to exploit its ability to inhibit HDACs. It had also been shown to possess antimetastatic and anticancer properties.48  The generation of the resulting complexes has led to some intriguing findings.

We reported the first examples of platinum-VPA complexes, namely trans-[Pt(VPA-1H)2(NH3)(py)] (12) and trans-[Pt(VPA-1H)2(py)2] (py = pyridine) (13) (see Figure 1.3).49  The inspiration behind their development was driven by evidence that VPA had been shown to exhibit synergistic cytotoxicity with cisplatin in a range of ovarian carcinoma cells, but also had the capacity to re-sensitise cells that had acquired resistance to cisplatin.50  We were also cognisant of the elegant work of Farrell and others who revived research into the use of planar trans-platinum amine (TPA) complexes as potential alternatives to classical cis-platinum(ii) drugs.10,51  For example, Farrell et al. had previously shown that the cytotoxicity profile of TPA complexes could be markedly enhanced by incorporating carboxylato moieties in place of the ‘traditional’ chlorido leaving ligands.51,52  Other studies had indicated that substitution of the ‘traditional’ non-leaving ammine or NH3 ligands with N-donor heterocyclic ligands such as py could markedly enhance the cytotoxicity of the resulting trans complexes. Despite the rationale behind the generation of our complexes, trans-[Pt(VPA-1H)2(NH3)(py)] (12) and trans-[Pt(VPA-1H)2(py)2] (13), in which the chlorido ligands in trans-[PtCl2(py)2] and trans-[PtCl2(NH3)(py)] had been replaced by VPA ligands, exhibited only marginally enhanced cytotoxicity against cisplatin-sensitive A2780 and cisplatin-resistant A2780cisR ovarian cells, when compared to cisplatin. Interestingly, later studies by other groups, as outlined below, demonstrated that changing the oxidation state of the platinum ion from +2 to +4, while retaining the VPA as a HDAC inhibitor ligand, could markedly enhance the efficacy of the resulting complexes.

Several teams have since independently reported platinum(iv)-VPA complexes. Tang, Shen, et al. developed a platinum(iv) complex incorporating a cisplatin framework with two axial VPA ligands, namely cis,cis,trans-diamminedichlorobisvalproato-platinum(iv) or VAAP (14) (Figure 1.3).53  They packaged it into PEG-PCL nanoparticles or dispersed into a Tween 80 surfactant in order to promote tumour cell uptake. Both the non-PEGylated and PEGylated VAAP derivatives were found to be highly cytotoxic, much more so than cisplatin, across multiple tumour cell lines. The ability of VAAP to induce HDAC inhibition was, however, not evaluated.53  In a parallel study, Osella et al. likewise developed the same platinum(iv)-VPA derivative, i.e. VAAP (14) (Figure 1.3).54  They also found the complex to be highly cytotoxic, in their case against four highly malignant and highly chemoresistant plural mesothelioma cell lines, again more so than cisplatin. The team were intrigued, however, when they assessed the cytotoxicity of an isomer of VAAP (14), namely cis,cis,trans-diamminedichloridobis(n-octanoato)platinum(iv) (19), in which the VPA ligands, which had been chosen for their potential to inhibit HDACs, were replaced with ‘innocent’ octanoate (OA) ligands. The latter complex exhibited similar and even sometimes greater efficacy than the platinum(iv)-HDAC inhibitor conjugate (14). This raised the important question as to whether or not the stoichiometric ratio of VPA : platinum (2 : 1) in VAAP (14) was sufficient to induce a synergistic outcome. They ultimately concluded that the improved cytotoxicity observed for the complexes could not be attributed to any synergistic contribution of the VPA ligands as HDAC inhibitors, rather that the VPA and OA ligands were altering the pharmacokinetic profile of the resulting complexes, leading to an increase in their lipophilicities and ultimately enhancing their accumulation into tumour cells.54 

Gibson, Brabec, et al. developed two further platinum(iv)-VPA complexes but, in their case, they employed an oxaliplatin scaffold to which they appended either one or two axial VPA ligands, (15 and 16) (Figure 1.3).55  Their choice of oxaliplatin as a core scaffold was in part driven by the fact that oxaliplatin, when given in combination with the HDAC inhibitor trichostatin A, resulted in an additive cytotoxic effect when tested against gastric tumour cells. Their complexes exhibited greater efficacy against both cisplatin-sensitive and cisplatin-resistant cell lines when compared to platinum(iv) analogues without biologically active axial ligands. Interestingly, their oxaliplatin-type platinum(iv)-VPA complexes were found to markedly downregulate HDACs, leading to a reduction in cellular levels of HDACs rather than direct inhibition of the HDAC enzymes. The enhanced cytotoxicity observed for these complexes was linked to this HDAC downregulation.55  This contrasted with the findings by Osella et al.54  which primarily attributed lipophilicity to the improved cytotoxicity profile of their cisplatin-type platinum(iv)-VPA complex, VAAP (14). Gibson et al. undertook a further study to probe these differing conclusions. They compared the efficacy of platinum(iv)-VPA complexes bearing a cisplatin equatorial core, (14 and 17) (Figure 1.3), against platinum(iv) analogues bearing ‘innocent’ biologically inert axial acetate ligands.56  Again, the VPA complexes were more cytotoxic than the complexes bearing the ‘innocent’ carboxylate ligands against the cell lines tested. The complexes also appeared to inhibit the expression of the HDAC protein, rather than inhibit HDAC directly. The complexes bearing the VPA ligands interfered with other cellular processes, including interfering with enzymes such as glutathione S-transferases. The team recognised that the enhanced lipophilicity bestowed on the complexes by the presence of the VPA ligands was also a positive contributory factor, accounting for the improved cytotoxicity observed for these complexes. They did not rule out the possibility that the platinum(iv)-VPA complexes could also be interacting with other biological targets, an important conclusion to highlight given the complex environment within any given cell.56 

Expanding their study, Gibson et al. developed platinum(iv) analogues of cisplatin, (14 and 17), oxaliplatin, (15 and 16), and trans-[Pt(n-butylamine)(piperidino-piperidine)Cl2]+(18) (see Figure 1.3), incorporating VPA in one or both axial positions. They also included platinum(iv) complexes (21–23) incorporating 4-phenylbutyrate (PhB) (20) (Figure 1.4) as axial ligands. Sodium phenylbutyrate, the sodium salt of PhB, is used to treat urea cycle disorders. It is also undergoing clinical trials as a treatment for cancer, haemoglobinopathies, motor neuron diseases and cystic fibrosis.57  The ligand PhB has also been shown to possess HDAC inhibition properties and it was on this premise that it was included in this study. The cytotoxicities of the resulting complexes (21–23) were compared to platinum(iv) complexes bearing ‘innocent’ carboxylate ligands. This was an interesting systematic study to identify not only the optimal platinum core scaffold but also the optimal axial HDAC inhibitor ligands, to ultimately optimise cytotoxic activity. In all cases, the complexes with a cisplatin core were more cytotoxic than those with an oxaliplatin core. The cis,trans,cis-[Pt(NH3)2(PhB)2Cl2] (22) (Figure 1.4) exhibited greatest cytotoxicity against all of the human cancer cell lines tested; lung, breast, pancreatic, kidney, prostate and colon carcinoma, along with melanoma. This complex was approximately 100-fold more cytotoxic than cisplatin and even more so when compared to cisplatin-type platinum(iv) derivatives bearing either two hydroxido, two acetato or two VPA ligands. Again, there appeared to be a positive correlation between lipophilicity, cellular accumulation and cytotoxicity of these complexes. Histone deacetylase inhibition appeared to be enhanced when the VPA or PhB ligands were coordinated to the metal scaffold, with the complexes being more potent HDAC inhibitors relative to VPA or PhB alone. It was clear by the end of this study that the cytotoxicity of these complexes was multi-factorial and that a ‘dual-functional’ view of these complexes was being overly simplistic.58 

Figure 1.4

Chemical structures of 4-phenylbutyric acid (PhB) (20) and platinum(iv)-PhB complexes (21–28).58,61 

Figure 1.4

Chemical structures of 4-phenylbutyric acid (PhB) (20) and platinum(iv)-PhB complexes (21–28).58,61 

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As key themes began to emerge, two of the main research groups working in this field (Osella et al. and Gibson, Brabec, et al.) began a collaborative study to better elucidate the mechanism of action giving rise to the enhanced cytotoxicity observed for the platinum(iv) complexes incorporating the axial ‘innocent’ OA ligands, over those containing branched isomers like VPA.59  The HDAC inhibition properties of OA are known to be significantly less than those of VPA, yet the platinum(iv) complexes bearing OA axial ligands were more cytotoxic than those containing VPA ligands against numerous cell lines.59  Accounting for this anomaly formed the focus of this study. The study validated that the platinum(iv) complex bearing two axial OA ligands was the most potent across several cell lines, significantly more so compared to cisplatin. This enhanced cytotoxicity could not be attributed to HDAC inhibition alone. Further studies to assess the capacity of the complex to either bind or methylate DNA and its impact on the mitochondria were undertaken to try to ascertain the influence of the OA ligands on the overall cytotoxicity profile of the complex. As anticipated, the presence of the OA ligands endowed the complex with greater lipophilicity which in turn enhanced its accumulation into tumour cells. Upon cellular accumulation, the complex was reduced to platinum(ii) with concomitant release of the OA ligands. The resulting platinum(ii) adduct was shown to bind DNA while the OA ligands were found not only to hypermethylate DNA but also to cause a reduction of the mitochondrial membrane potential.59  DNA methylation is known to play a key role in gene expression associated with carcinogenesis, cancer progression and metastasis.60 

It is interesting to note that what were perceived as ‘innocent’ or ‘biologically inactive’ OA ligands were not at all ‘innocent’. The platinum(iv) complex bearing two axial OA ligands (19) (Figure 1.3), was significantly more cytotoxic than the complexes incorporating the HDAC inhibitors, VPA and PhB. While the results were unexpected, the methodical approach of the team led to interesting findings as indicated above and highlights the need for latitude in interpreting results.

More recently, Erxleben, Montagner, et al. developed a related class of platinum(iv)-PhB complexes. In their case, they employed a platinum scaffold incorporating the N,N-non-leaving ligand of oxaliplatin and the O,O-leaving ligand of carboplatin, to which they appended the PhB ligand in one or both axial positions.61  Their library consisted of complexes bearing either two axial PhB ligands (24), or one PhB and either hydroxide (25), acetate (26), succinate (27) or benzoate (28) in the other axial position (see Figure 1.4). The complex which demonstrated greatest efficacy turned out to be the derivative containing a PhB in one axial position and benzoate in the other (28) (Figure 1.4), with IC50 values lower than carboplatin against all the cell lines tested. Of the complexes developed, there appeared to be a direct correlation between cytotoxicity and cellular accumulation and HDAC inhibition with the lead complex (28) exhibiting highest accumulation and HDAC inhibition ability.61 

A slightly different approach by Gandin, Gibson, et al. involved the development of platinum(iv) analogues of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (Pt56MeSS) (29) (Figure 1.5). Unlike classical platinum(ii) drugs, this Pt56MeSS complex does not contain any labile ligands and is thus not expected to undergo the type of substitution reactions associated with classical platinum(ii) drugs. Rather, it bears two non-leaving bidentate N,N-donor ligands. Although it breaks the structure activity relationship associated with classical platinum(ii) drugs, the compound has been shown to be highly cytotoxic towards cisplatin-resistant and oxaliplatin-resistant cell lines.62  A proposed target for this complex is the mitochondrion. In this study, both non-bioactive, lipophilic and bioactive (VPA and PhB), axial ligands (30–35) were tethered to the platinum(iv) base of Pt56MeSS (29) (Figure 1.5).62  This new library of platinum(iv) derivatives had, on average, greater efficacy over cisplatin and possessed either comparable or lower efficacy when compared to Pt56MeSS itself. Interestingly, the presence of the axial HDAC inhibitor ligands appeared to have little or no influence on the cytotoxicity of the resulting complexes. For example, the average IC50 value for Pt56MeSS across seven human tumour cell lines (lung (H157), colon (HCT-15), breast (MCF-7), thyroid (BCPAP), ovarian (2008) and pancreatic (BxPC3)) was 1.24 µM as compared to 2.34 µM for the platinum(iv) complex bearing one OAc and one PhB ligand (33), 1.41 µM for the complex bearing two PhB ligands (34) and 2.00 µM for the complex bearing one OAc and one VPA ligand (35).62  There did not appear to be any correlation between cellular accumulation and cytotoxicity, nor HDAC inhibition, in the case of VPA and PhB axial ligands. Furthermore, these results were in direct contrast with previous reports of platinum(iv) complexes incorporating a cisplatin scaffold and bearing PhB axial ligands, where there was an order of magnitude difference in cytotoxicity recorded. For example, the IC50 value for the platinum(iv) complex bearing two PhB axial ligands and containing a cisplatin core (22) (Figure 1.4), was 0.18 µM against breast (MCF-7) cancer cells and 0.31 µM against colon (HCT-15) cells in contrast to IC50 values of 2.22 µM and 0.69 µM for 34 against the same cell lines, respectively. That said, the core frameworks are different, which probably accounts for the differences observed.62 

Figure 1.5

Chemical structures of platinum(iv) analogues (30–35) of Pt56MeSS (29).62 

Figure 1.5

Chemical structures of platinum(iv) analogues (30–35) of Pt56MeSS (29).62 

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Cyclooxygenase (COX) enzymes are amongst the most widely studied and best understood of all the mammalian oxygenases. Three isoforms of COX have been identified; COX-1, COX-2 and COX-3.63  They catalyse the conversion (bis-dioxygenation and subsequent reduction) of arachidonic acid to prostaglandin G2 and H2 (PGG2 and PGH2), mediators of inflammatory and anaphylactic reactions. For this reason, they have been the subject of intense investigation and, already, a number of COX inhibitors are in clinical use to treat pain and inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) are one such class that have proven highly successful in this regard. These NSAIDs include, but are by no means limited to, indomethacin (36), ibuprofen (37) and aspirin (38) (Figure 1.6), the drugs of relevance to this section.

Figure 1.6

Chemical structures of indomethacin (36), ibuprofen (37) and aspirin (38) and their platinum(iv) complexes (39–43).67,68,72–75 

Figure 1.6

Chemical structures of indomethacin (36), ibuprofen (37) and aspirin (38) and their platinum(iv) complexes (39–43).67,68,72–75 

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Interestingly, there is a significant body of evidence in the literature to support the hypothesis that overexpression of the COX-2 isoform is a driver of carcinogenesis and, conversely, inhibition of COX-2 is an attractive drug target for cancer prevention and therapy. For example, COX-2 has been shown to be constitutively expressed throughout breast cancer development, from the detection stage to cancer progression and metastases. It has also been shown that mammary carcinogenesis (which includes mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis and immunosuppression) has been linked to COX-2-mediated prostaglandin E2 (PGE2) biosynthesis. There is also evidence to support that COX-2 inhibitors decrease the risk of breast cancer in female patients without this disease and, similarly, decrease the incidence of recurrence risk and mortality in patients with breast cancer.64  Overexpression of COX-2 is not limited to breast cancer cells. Other tumour types which overexpress COX-2 include skin, oesophagus, stomach, colorectal, pancreas, and bladder.65  It is also interesting to note that a number of COX inhibitors, when used in combination with established cancer drugs, including cisplatin, paclitaxel and doxorubicin, act in a synergistic manner.66  To the best of our knowledge, Neumann et al. were the first to report platinum(iv)-NSAID complexes. They rationally designed symmetrical platinum(iv) prodrugs consisting of either a cisplatin(39 and 41, respectively) or oxaliplatin core scaffold (40 and 42, respectively) and incorporating either indomethacin (39 and 40) or ibuprofen (41 and 42) in the axial positions (see Figure 1.6).67,68 

Indomethacin is a non-specific COX inhibitor. It has been found to induce a profound reduction in the ability of breast cancer cells to invade and degrade the extracellular matrix gel.69  The cisplatin-like indomethacin (39) and ibuprofen (41) derivatives were significantly more cytotoxic compared to cisplatin. They were also highly cytotoxic against cisplatin-resistant MDA-MB-231 breast cancer cells. When tested against two tumour cells with different levels of COX-2 expression, namely the cisplatin-sensitive colorectal HCT 116 carcinoma cells, which do not express COX-2, and cisplatin-resistant breast MDA-MB-231 adenocarcinoma cells, which exhibit high constitutive COX-2 expression, the cytotoxicities of the complexes did not differ significantly. Interestingly, despite comparable cytotoxicities, the indomethacin complexes exhibited strong COX inhibitory activity in contrast to the ibuprofen analogues, which exhibited poor COX inhibition. The team concluded that there did not appear to be a correlation between cytotoxicity and COX inhibition, nor to their potency as NSAIDs, nor to the levels of COX expression in these cells. The team ultimately concluded that the change in the physicochemical properties of the complexes, resulting from the presence of the lipophilic NSAIDs, facilitated greater uptake of the complexes into the tumour cells and it was this property that accounted for the increase in cytotoxicity relative to cisplatin.67 

A follow-up study by the same team sought to validate their hypothesis. Employing the same NSAID ligands, they developed both platinum(iv)-NSAID conjugates, this time with an oxaliplatin base (40 and 42) (Figure 1.6) as well as the analogous platinum(ii) derivatives for comparative purposes. In all cases, the platinum(iv)-NSAIDs exhibited more potent cytotoxicities relative to the platinum(ii) analogues. The former were also able to overcome cisplatin resistance. The team concluded that COX-mediated pathways were not responsible for the cytotoxicity of these complexes.68 

Aspirin (acetylsalicylic acid) (38) (Figure 1.6) is a hugely successful drug used globally as an analgesic and anti-pyretic agent. It is also commonly used for cardiovascular prophylaxis. There is considerable evidence in the literature citing its potential as a cancer chemopreventive agent, particularly against colorectal cancer (CRC), with several studies showing a drop in the incidence of CRCs following long-term treatment with low doses of aspirin.70,71 

Dhar et al. developed Platin-A, an asymmetric platinum(iv) prodrug incorporating one aspirin axial ligand (43) (see Figure 1.6).72  Another group, led by Liu, reported this same complex a few months later, but they referred to it as Asplatin.73  The study of Dhar et al. showed that, upon tumour cell accumulation and following the proposed ‘activation by reduction’ process, Platin-A released cisplatin and one equivalent of aspirin. It was found to be highly cytotoxic against androgen-unresponsive prostate PC3 and DU145 cells, with a cytotoxicity profile comparable to that of cisplatin. Aspirin alone was not cytotoxic. The complex was also later shown to possess anti-inflammatory properties mediated via COX-2 inhibition.74  The study by Liu et al. screened this same complex, Asplatin (43) (Figure 1.6) against a range of additional tumour cell lines (cervical HeLa, breast MCF-7, liver HepG2, lung A549, A549R) in addition to normal human fibroblast cells.73  They found Asplatin to be highly cytotoxic across all the tumour cells, including chemoresistant cells, and more so than cisplatin. Asplatin was found to retain its cytotoxic activity, better than cisplatin, when tested in vivo in mice bearing lung A549 tumours, while also exhibiting a better safety profile. They also demonstrated that the complex could be reduced to its cisplatin core and aspirin following treatment with equimolar concentrations of ascorbic acid, supporting the ‘activation by reduction’ hypothesis proposed by Dhar et al. While the team demonstrated that Asplatin could bind DNA, they did not assess its ability to inhibit COX activity.73  They did, however, in a later study, report evidence suggesting that the complex modulated the cellular response to the platinum cytotoxic agent. Through apoptosis analysis and gene expression studies, the complex was shown to promote apoptosis via the BCL-2-associated mitochondrial pathway. While BCL-2 was shown to be downregulated, BAX and BAK were found to be upregulated, and this combination caused an increase in the permeability of the mitochondrial outer membrane. This change in permeability facilitated the release of cytochrome C into the cytosol, promoting apoptosis mediated via caspase activation processes.75  This is one of only a few studies reported to date in which gene expression analysis was exploited in order to more fully elucidate the mechanisms underpinning the anticancer properties of platinum complexes.

Ethacrynic acid (Edecrin) (44) (Figure 1.7) is in clinical use as a loop diuretic which, when administered, leads to prompt and excessive diuresis. Its primary mode of action has been attributed to its ability to inhibit the activity of the Na+-K+-2Cl symporter in the thick ascending limb of the loop of Henle.76  Ethacrynic acid has also been shown to possess potent glutathione S-transferase (GST) inhibition activity.77,78  Glutathione S-transferases are considered one of the most important classes of detoxification enzymes that work to remove harmful chemicals from the body via phase II biotransformations.78  They have been specifically shown to play a part in the detoxification of platinum anticancer drugs and, in fact, certain cisplatin-resistant tumours have been shown to overexpress these enzymes.79  These GST enzymes catalyse the nucleophilic S-conjugation between the thiol group of glutathione and xenobiotics, including cisplatin, which facilitates their elimination from the body via the mercapturic acid pathway.80 

Figure 1.7

Chemical structures of ethacrynic acid (44), ethacraplatin (45)81  and another platinum(iv)-ethacrynate complex bearing only one ethacrynate ligand (46).82 

Figure 1.7

Chemical structures of ethacrynic acid (44), ethacraplatin (45)81  and another platinum(iv)-ethacrynate complex bearing only one ethacrynate ligand (46).82 

Close modal

Given the affinity of the platinum ion for ‘soft’ nucleophiles, including those containing thiol groups, it is not surprising that they represent a viable target for GST-mediated detoxification. Dyson et al. developed ethacraplatin (45) (Figure 1.7), a platinum(iv) complex consisting of a cisplatin core with ethacrynate ligands in both axial positions.81  They proposed that the presence of the ethacrynate ligands would endow the complex with greater lipophilic properties and that this would enhance its uptake into tumour cells, more so than cisplatin. They also suggested that, upon tumour cell entry, the complex would be reduced which would result in the release of its GST inhibitor ligands, thus inhibiting any platinum drug detoxification. Cisplatin, which would be simultaneously released, would therefore be free to interact with its biological target, DNA.81 

When screened against a series of tumour cell lines, including cisplatin-resistant breast, lung and colon carcinomas, ethacraplatin was indeed found to be significantly more cytotoxic compared to cisplatin alone. Follow-up biochemical and structural studies were conducted by the same group in an attempt to better understand the mode of action of ethacraplatin.81  The group specifically chose GST P1-1 as their protein target for this study, given its importance in the mercapturic acid detoxification pathway. Ethacraplatin was indeed shown to bind to this target at the dimer interface, with the ethacrynate ligands interacting at both active sites. Interestingly, the cisplatin scaffold was found to be sandwiched between two bridging cysteine residues at the dimer interface, suggesting that it would remain bound and therefore not free to bind its target, DNA. While this study demonstrated evidence of strong and irreversible enzymatic inhibition by ethacraplatin (45), it also revealed that the cytotoxicity could not be attributed to platinum-DNA-binding interactions as originally anticipated.81 

It was suggested more recently that cisplatin release from ethacraplatin was not sufficiently fast enough, due to its low reduction rate, to facilitate any platinum-DNA binding. With this in mind, Ang, Montagner, Nowak-Sliwinska, Dyson, et al. recently developed an ethacraplatin analogue in which they replaced one of the ethacrynate ligands with a hydroxido ligand (46) (Figure 1.7).82  This monofunctionalised complex was shown to overcome the aforementioned limitation of ethacraplatin. The ethacrynate ligand was readily released in vitro from the platinum(iv) framework, with concomitant release of the cytotoxic platinum(ii) agent. The complex was shown to inhibit GST in a non-competitive way. Despite losing one of the ethacrynate ligands, the complex retained its cytotoxicity against both cisplatin-sensitive and cisplatin-resistant tumour cells. Its potential as a new class of dual functional anticancer agent was validated using an in vivo study which demonstrated that the complex induced ∼80% inhibition of tumour growth in a human ovarian carcinoma tumour model.82 

2,2-Dichloroacetic acid (DCA) (47) (Figure 1.8) is an intriguing small molecule with various therapeutic applications. For example, DCA is not only used to treat inherited mitochondrial disorders that result in lactic acidosis, but also pulmonary hypertension.83  It is also under investigation as an anticancer agent given its capacity to reverse the ‘Warburg effect’.83  This effect refers to the over-reliance of cancer cells on cytosolic aerobic glycolysis to generate energy, in contrast to healthy cells which primarily rely on mitochondrial oxidative phosphorylation.84  Tumour cells can therefore be targeted while leaving normal cells unharmed.

Figure 1.8

Chemical structures of 2,2-dichloroacetic acid (DCA) (47) and platinum(ii) complexes bearing DCA derivatives (48–53)88,89  and the platinum(iv)-DCA complex, mitaplatin (54).90 

Figure 1.8

Chemical structures of 2,2-dichloroacetic acid (DCA) (47) and platinum(ii) complexes bearing DCA derivatives (48–53)88,89  and the platinum(iv)-DCA complex, mitaplatin (54).90 

Close modal

This simple DCA molecule works by modulating carbohydrate metabolism at the level of the multi-enzyme mitochondrial pyruvate dehydrogenase complex (PDC). This complex, which is present in the mitochondrial matrix, acts as a gatekeeper by linking cytoplasmic glycolysis to the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS).83  Pyruvate dehydrogenase kinases (PDK 1–4) act by inhibiting the activity of this complex while pyruvate dehydrogenase phosphatases (PDP 1 and 2), in contrast, maintain PDC in its unphosphorylated, active state. Certain cancer cells overexpress these PDK isoforms and this leads to a reduction in PDC activity.85  Dichloroacetate, which is a structural analogue of pyruvate, acts by inhibiting PDKs, thus stimulating PDC and OXPHOS activity.86,87  Several studies have indicated that this increase in OXPHOS activity leads to the production of reactive oxygen species by the mitochondrial respiratory chain which, following other downstream changes in mitochondrial function, leads to selective apoptosis of tumour cells. This effect has also been observed in rodents bearing tumour xenografts.86 

Li et al. developed two interesting platinum(ii) complexes bearing ligands which contain a DCA derivative as part of their framework. Specifically they tethered the DCA fragment to cyclobutane-1,1-dicarboxylate via an ester bond linkage which resulted in the formation of 3-dichoroacetoxylcyclobutane-1,1-dicarboxylate. Cyclobutane-1,1-dicarboxylate was an interesting choice given that it is the O,O-bidentate leaving ligand in carboplatin. It was this derivatised ligand that they then complexed to platinum(ii) centres. Two novel mixed-ammine/amine platinum(ii) complexes (48 and 49) (Figure 1.8) were formed.88  Although the complexes exhibited marked cytotoxic selectivity towards cancer cells (including cisplatin-resistant SK-OV-3 cells) over BEAS-2B normal cells, their further development was limited due to their poor aqueous solubility.88 

In order to address this shortcoming, the same group developed four additional diam(m)ine platinum(ii) complexes. These complexes retained the original carboplatin-like dicarboxylate DCA-containing leaving group but the N-donor non-leaving ligand(s) were modified (50–53) (Figure 1.8). Following cytotoxicity screening against A549, SK-OV-3 and SK-OV-3/DDP (cisplatin resistant) cell lines, the oxaliplatin analogue, 51, was found to be not only the most potent but also ∼10 times more water soluble than the complexes reported previously. It was found to be 60 times more cytotoxic compared to carboplatin against the A549 cells, six times more so against SK-OV-3 cells and >15 times more cytotoxic against the SK-OV-3/DDP cells which are cisplatin resistant. This complex was also shown to release its moiety via hydrolysis of the ester bond under physiological conditions.89 

There is one example to date of a platinum(iv)-DCA complex, namely mitaplatin (54) (see Figure 1.8).90  This complex, which was developed by Dhar and Lippard, contains a cisplatin equatorial base with two axial DCA ligands. Cytotoxicity screening against eight cancerous cell lines revealed that, in addition to having comparable cytotoxicity to cisplatin, the complex exhibited equal or improved cytotoxicity compared to many of the platinum(iv) complexes that had been reported at that time. It was also found to be more cytotoxic than DCA alone.90  The fact that mitaplatin (54) was shown to have low toxicity against human fibroblast cells suggested that the presence of the DCA ligands may be impacting on its cytoselectivity profile. This cytoselectivity provides preliminary evidence to support their drug design strategy that cells dependent on glycolysis would be targeted. The complex, 54, induced DNA damage analogous to the type of damage induced by cisplatin, which supports an ‘activation by reduction’ mode of action. Liang et al. provided evidence that mitaplatin specifically targets the mitochondria. They demonstrated that mitaplatin activated a downstream mitochondrial-dependent cell death in tumour cells resistant to cisplatin. It was found to act as a metabolic modulator by downregulating the phosphorylation of pyruvate dehydrogenase. This led to a glycolytic shift back to oxidative phosphorylation by increasing the uptake of acetyl-CoA into the mitochondria.91 

Platinum(iv) complexes, as stated earlier, are expected to be kinetically inert. This, however, was found not to be the case for mitaplatin (54) (Figure 1.8). Gibson et al. revealed that mitaplatin was not very stable under biological conditions, including cell culture media. They showed that 50% of mitaplatin had undergone hydrolytic degradation after only 2 hours.92  Given the cytotoxicity profile of mitaplatin, the group concluded that the uptake of mitaplatin into tumour cells must be faster than its rate of hydrolysis and that mitaplatin hydrolysis products, in addition to mitaplatin, may be responsible for the cytotoxicity observed. Encapsulation of mitaplatin in a nanoparticle formulation was later shown by Lippard et al. to increase its efficacy in an in vivo mouse xenograft model of triple-negative breast cancer.93 

While there is plenty of evidence now in the literature to support a multi-targeted approach in the quest to bring forward a new drug class, Gibson et al. brought this to another level in that they rationally designed and developed a dinuclear ‘quadruple action’ platinum(iv) prodrug. This complex contains two platinum(iv) centres, which, upon reduction, release simultaneously four different bioactive moieties; namely, cisplatin, Pt56MeSS (29) (Figure 1.5), and the clinically approved DCA (47) (Figure 1.8) and PhB (20) (Figure 1.4) ligands.94  One platinum(iv) centre is contained within a cisplatin scaffold with one monodentate DCA ligand and one bridging dicarboxylate ligand. The DCA ligand was chosen for its PDK inhibitory properties. The other platinum(iv) centre is derived from a non-DNA-binding Pt56MeSS core (29) (Figure 1.5) previously shown to act on the mitochondria. The coordination sphere around this platinum(iv) centre is completed by one axial monodentate PhB HDAC inhibitor ligand and the bridging dicarboxylate ligand. A number of compounds were also synthesised serving as reference standards for biological testing. These included the platinum(ii) complexes cisplatin, oxaliplatin and Pt56MeSS (29) (see Figure 1.5), the monomeric dual action platinum(iv) complexes (56) and (57) and the dimer (58) (Figure 1.9). The activity of the dinuclear ‘quadruple action’ platinum(iv) prodrug (55) was compared to these complexes across a range of human cancer cell lines, including ovarian, cervical, lung, colon and pancreatic cancer cells.94 

Figure 1.9

Chemical structures of a ‘quadruple action’ platinum(iv) prodrug (55)94  and its mononuclear (56 and 57) and dinuclear (58) adducts (with DCA highlighted in green and PhB in blue).

Figure 1.9

Chemical structures of a ‘quadruple action’ platinum(iv) prodrug (55)94  and its mononuclear (56 and 57) and dinuclear (58) adducts (with DCA highlighted in green and PhB in blue).

Close modal

Of the complexes assessed, the ‘quadruple action’ complex (55) was significantly more cytotoxic compared to the dual functioning or single agents, suggesting that the bioactive ligands present within the complex framework were contributing to the enhanced cytotoxicity observed. It was also significantly more cytotoxic compared to cisplatin alone and oxaliplatin alone.

The ‘quadruple action’ complex, in particular, exhibited remarkable cytotoxic activity against KRAS-mutated pancreatic (MIAPaCa-2) and colon (LoVo) cancer cell lines. For example, the complex had an IC50 value of 0.06 ± 0.01 µM against MIAPaCa-2 cells and 0.02 ± 0.005 µM against LoVo cells. These IC50 values were between 200- and 450-fold lower than those for cisplatin against the same cell lines (where the IC50 value for cisplatin against MIAPaCa-2 cells was 13.45 ± 2.45 µM and against LoVo cells was 9.12 ± 0.005 µM). The ‘quadruple action’ complex was also 40‐fold more selective towards KRAS-mutated cells compared to non‐cancerous cells. KRAS represents a major oncogene associated with aggressive cancers.95  These cancers tend to have poor prognosis and to date there does not appear to be any effective drug treatment. The activity of 55 was also assessed against HCT-15, BxPC3 and KRAS-mutated PSN1 spheroid models. These 3-D cell cultures are used to more closely mimic the in vivo environment of tumour cells. In all cases, the complex was more cytotoxic compared to cisplatin and compared favourably to oxaliplatin in the non-KRAS-mutated cells. Given the sound rationale behind the development of this quadruple action complex, the team went on to establish that, upon cellular activation, it had the capacity to covalently modify DNA following release of its cisplatin core. It was also shown to impact on mitochondrial function and inhibit HDACs, validating the original design strategy.

Cancer is a multi-factorial disease which continues to represent a global health challenge. Platinum drugs remain a cornerstone in cancer drug treatment regimens but they have shortcomings, including toxic side effects and resistance issues. The rational design and development of new platinum drugs that can overcome these drawbacks remains a thriving field of research.

In recent years, there has been a tangible shift in focus towards designing platinum drugs that contain either vectors to target tumour cells (thus reducing unwanted side reactions and consequently dose-limiting toxic side effects), or platinum drugs that can target more than one cellular entity. The latter approach may lead to new ‘multi-targeted’ drug candidates with a mechanism of action different from clinically used platinum drugs and may thus overcome resistance issues that can plague some cancer treatment regimens.

This chapter provides an overview of recent developments in the design and development of a relatively new type of ‘multi-targeted’ platinum drug complex. These complexes, in addition to targeting DNA, incorporate clinically approved drugs, or derivatives thereof, as ligands which target other cellular entities. Interestingly, while there is a sound rationale behind repurposing existing drugs as outlined in the introduction to this chapter, those drugs to date that have been tethered to platinum have not been chosen for this purpose. Rather, they have been selected because they have, in their own right, exhibited anticancer activities, albeit that some are in clinical use for other indications.

There is no doubt that there are advantages to this approach. Knowing the pharmacokinetic profile of these drug ligands which have already been approved for clinical use can better inform the drug design strategy. However, due cognizance should also be given to the therapeutic advantages of employing drug molecules as ligands over their known toxicity profiles.

Secondly, incorporating two drug entities into one drug molecule allows for greater pharmacokinetic control, including delivery of a single drug entity to its target site. Having one drug instead of two may also potentially reduce drug costs as well as increase patient compliance.

We have also highlighted numerous examples of platinum drug complexes in which the incorporation of the drug, or drug derivative, has clearly endowed the resulting complexes with enhanced in vitro cytotoxicity compared with cisplatin, one of the gold standards in chemotherapeutic regimens. Many of the complexes highlighted in this chapter have demonstrated great potential, particularly against tumour cells that are known to be resistant to platinum drug treatments. Whether the potent cytotoxic properties of these promising agents can translate to in vivo cancer xenograft models remains to be explored, in most cases.

In conclusion, there is no doubt that with due cognisance, one can carefully select a clinically approved drug to serve as a ligand to enhance the therapeutic efficacy of existing platinum drugs. In vivo studies will play a critical role in determining the potential of these and any new complexes of this type if they are to advance from pre-clinical to clinical development. The literature is rich with examples of drugs that can be further exploited as drug ligands. Combining these drugs into a metallodrug framework may well form the basis of a new drug class which may offer advantages over existing therapeutic regimens.

Bel

Belinostat

COX

Cyclooxygenase

VAAP

cis,cis,trans-Diamminedichlorobisvalproato-platinum(iv)

DCA

Dichloroacetate

HAT

Histone acetyltransferases

HDAC

Histone deacetylases

GST

Glutathione S-transferase

TCA

Mitochondrial tricarboxylic acid

NHL

Non-Hodgkin lymphoma

NSAIDs

Non-steroidal anti-inflammatory drugs

NHDF

Normal human dermal fibroblast

OA

Octanoato

OXPHOS

Oxidative phosphorylation

PhB

4-Phenylbutyrate

py

Pyridine

SAHA

Suberoylanilide hydroxamic acid

SubH

Suberoyl-bis-hydroxamic acid

TPA

trans-Platinum planar amine

VPA

Valproic acid, 2-propylpentanoic acid

This material is based upon works supported by the Science Foundation Ireland under Grant Nos. [11/RFP.1/CHS/3095] and [12/TIDA/B2384] and [17/TIDA/5009]. This work has also been funded by the RCSI under the Apjohn Scholarship programme. Funding under the Programme for Research in Third-Level Institutions and co-funding under the European Regional Development fund (BioAT programme) is also acknowledged. The authors would also like to acknowledge COST CM1105 and CA13135 for providing a platform to progress fruitful collaborations.

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