As well as 16 electron square planar complexes, platinum can also form stable 18 electron octahedral compounds with a variety of ligands. These Pt (IV) complexes can be synthesised through two different routes, oxidation of a Pt (II) complex and direct synthesis. Both routes are explored in this project and are further discussed in Chapter 3.
146 147
Figure 1.21: Tetraplatin 146 and Iproplatin 147, both Pt (IV) octahedral complexes which
reached Phase I clinical trials but later discontinued due to high toxicity.111
As seen in Figure 1.21, the Pt (IV) complexes contain additional functional groups (compared to their Pt (II) analogues) above and below the plane of the traditional equatorial leaving and non-leaving groups. These additional functional groups are normally referred to as the “axial groups”. One of the primary advantages identified by Hall et al that Pt (IV) complexes present is the large number of chemical and biological variations that can be achieved by substituting different groups on the axial positions.112
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The axial and equatorial ligands determine a large array of anti-tumour mechanisms, unfortunately the full extent of these mechanisms have yet to be studied in extensive detail. In studies carried out by Choi et al it was been found that Pt (IV) compounds are generally inert towards ligand substitution reactions relative to their Pt (II) analogues. In order to bind to DNA it has been proposed that they must first be reduced to their Pt (II) analogue. It was also found that they are reduced by both extracellular and intracellular agents such as ascorbate, glutathione and other protein sulfhydryls.113,114 The proposed mechanism for the reduction of Pt (IV) complexes is illustrated in Figure 1.22.
Figure 1.22 shows the fate of a typical Pt (IV) chloride complex in-vivo. The extra cellular chloride concentration outside the cell (left hand side) (100 mM) is much higher than the concentration inside the cell, intracellular (4 mM). The molecule passes into the cell in response to the chloride concentration gradient through a process similar to osmosis.115 Because the Pt (IV) drugs need to be reduced prior to binding to the target DNA, these complexes are therefore often called prodrugs.116
Reduced
Hydrolysed Can’t leave the cell
Figure 1.22: The mechanism of Pt (IV) reduction in-vivo of a typical chloride based
octahedral complex, the cell membrane is shown in the middle in blue.115
Further work by Choi et al on cyclometallated Pt (IV) complexes has shown that the platinum complexes with hydroxo axial ligands reduced very slowly while those with chloro axial ligands reduced very fast. Acetate ligands generally show a moderate reduction rate, while certain complexes reported were not reduced under the conditions investigated.
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It was also noted that reduction is favoured by the presence of electron withdrawing axial ligands and bulky axial ligands. Electronegative axial ligands, such as chlorides, increased the reduction rate by promoting destabilisation of the Pt (IV) state, due to electron- withdrawing effects. Complexes with bulky axial ligands also promote destabilisation of the Pt (IV) state, which results in a faster reduction to the more stable Pt (II) state.113
In the presence of reducing agents such as glutathione and ascorbate, Pt (IV) complexes generally show enhanced reactivity towards DNA. This supports the proposal that the Pt (IV) complexes need to be reduced to their active Pt (II) analogue in order to have anti- cancer activity.112 However, in certain cases the parent Pt (IV) complex is actually more active than its analogous Pt (II) complex. Choi et al and Galanski et al have both reported some examples of Pt (IV) complexes which can bind to DNA and RNA fragments without being reduced (Figure 1.23).113,117
148 149
Figure 1.23: The structure of the Pt (IV) complex [enPt(OCOCH3)4] 148 and the GMP
disodium salt 149 used to form the platinum bio-adduct.117
Galanski and Bernhard have created a Pt (IV)-5’-GMP bio-adduct species in their studies from the above salt 148 and Pt (IV) complex 149, Figure 1.23. They have also confirmed the stability of the species over several weeks by (1H and 15N) NMR spectroscopy. Interestingly, the analogous Pt (II) reduced species was not detected in the final products.117
One particular Pt (IV) complex which has attracted quite a lot of interest in the past number of years is “satraplatin” (bis-aceto-ammine-dichloro-cyclohexylamine platinum (IV)) or JM-216, first reported by Kelland et al in 1993, Figure 1.24.118 Initial in-vitro studies on Satraplatin found it to be around 3 fold more potent than cisplatin in some cell lines and it had 4.2 fold better intracellular accumulation compared to cisplatin.118 Also, in Phase I and II clinical trials it was observed to have no cardiac, renal, heptatic, or neurologic toxicity.119 More recently it has proceeded to Phase III trials in combination with other therapies such as Docetaxel where moderate success has been achieved.120
Pt OCOCH3 N H2 OCOCH3 H2 N OCOCH3 OCOCH3 H H OH OH H H O (NaO)2OPO N N H HN N O H2N
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Although satraplatin is not vastly beneficial over existing treatments, in all the clinical trials one feature has made it very attractive; it is orally active.119,120 The traditional platinum agents, cisplatin, carboplatin, and oxaliplatin are all administered intravenously and are associated in varying degrees with neurotoxicity, nephrotoxicity, myelosuppression, and oto- toxicity. As an oral based drug, Satraplatin has convenient dosing and so far has not been associated with the same level of toxicity as the currently approved platinum based anti- cancer compounds. Currently it remains in clinical trials in the United States but given the lack of an overall survival benefit, satraplatin has not yet received approval by any regulatory authority.121
150
Figure 1.24: The structure of Satraplatin 150, a Pt (IV) complex that has reached phase III
clinical trials and will be discussed further in Chapter 3.