The enduring structure-activity relationship for platinum antitumor agents is that the trans geometry is inactive. Yet substitution of NH3 in trans-[PtCl2(NH3)2] by a wide variety of ligands produces compounds with micromolar cytotoxicity similar to that of cisplatin. Use of a planar amine group in trans-[PtCl2(NH3)L] or trans-[PtCl2L2] (L = pyridine, thiazole, quinoline, isoquinoline etc) gives compounds with equal in vitro cytotoxicity to cisplatin and collateral sensitivity to both cisplatin and oxaliplatin [[1], [2], [3]]. Similarly, use of aliphatic amines such as piperidinopiperidine and piperidine, [4], or iminoethers give compounds with micromolar cytotoxicity similar to that of cisplatin [1]. The Pt(IV) compound, (trans,trans,trans-[PtCl2(OH)2(NH3)(cyclohexylamine)]) (JM 335), also showed in vivo antitumor activity superior to the trans-Pt(II) precursor [5,6]. However, consistent in vivo antitumor activity for a series of transplatinum complexes has proven elusive. Despite the clinical success of cisplatin and its derivatives, dose-limiting toxic side effects allied to inherent and acquired resistance against approved platinum compounds means there is a continued need and opportunity for the development of new generations of antitumor platinum agents [7]. In this brief review paper, we report on in vivo antitumor activity of the transplatinum geometry of the generic series [trans-Pt(O2CR)(NH3)(planar amine)] (O2CR – carboxylate, planar amine = isoquinoline).

Introduction of a planar amine in trans-[PtCl2(NH3)L] or trans-[PtCl2L2] gives a broad series of possible TPA (transplanaramine) structures characterized by cross sensitivity to cisplatin (activity in cisplatin-resistant cell lines) and a clearly distinct cytotoxicity profile assessed through the NCI COMPARE program and clustered image maps [2,3,8]. However, the substitution of the neutral aromatic amine for NH3 resulted in reduced aqueous solubility. Use of mutually trans carboxylate ligands in trans-[Pt(O2CR)2(NH3)L] or trans-[Pt(O2CR)2L2] improved many desired properties such as enhanced aqueous solubility, resistance to plasma protein binding and significant reduction in hydrolysis rates while maintaining cytotoxicity equivalent to the parent chloride complexes [[9], [10], [11], [12], [13]]. The mutually weak trans influence of the carboxylate ligands is a novel approach to reducing substitution lability along a trans-PtX2 axis and results in significantly less reactive compounds when X = O2CR instead of X = Cl. In this contribution we summarize briefly the biological activities of transplatinum complexes containing the [PtN2O2] donor set as a class and demonstrate their in vivo activity by systematic manipulation of the pharmacokinetic factors determining this activity. For in vivo studies, we chose a small, closely related series differing only in the nature of the carboxylate ligands trans-[Pt(O2CR)2(NH3)(isoquinoline)] (TPA 1–3 where O2CR = acetate, hydroxyacetate and D-lactate, Fig. 1. The relatively substitution-labile formate analog is compared as appropriate [13]. From previous studies, the isoquinoline planar amine ligand on TPA compounds was shown to exhibit higher cytotoxicity toward tumor cells as compared to other planar amine ligands (possibly due to higher steric hindrance and DNA stacking effect induced by its relatively large heterocycle structure [8,10,11]. The results show that the moderately reactive TPA2 and TPA3 (O2CR = hydroxyacetate and D-lactate) respectively show similar metabolic stability in comparison with the more inert acetate-containing TPA1, exhibited higher cytotoxicity and cellular accumulation and were more effective in vivo. Cell cycle effects and ethidium bromide fluorescence quenching assays were also examined to observe differences in cytotoxic profiles of TPA compounds in comparison to cisplatin.