Modulation of transplanaramine platinum complex reactivity by systematic modification of carrier and leaving groups

摘要

Transplatinum planaramine complexes with carboxylate ligands as leaving groups, trans-[Pt(O_2CR)_2(L)(L0)] (L = L0 = pyridine; L=NH3, L0 = pyridine, isoquinoline, thiazole, quinoline, etc.), are potential anticancer complexes with cytotoxicity in some cases equivalent to that of cisplatin. The carboxylate complexes are, as a family, very water-soluble and surprisingly stable towards hydrolysis – resembling carboplatin in their reactivity. Their pharmacological properties can be systematically modified by steric and electronic effects of the donor groups as well as in the leaving carboxylate ligands. Previously, we have recognized the leaving group formate as having appropriate kinetics for bioligand substitution [1]. In this paper we directly compared the effect on biological properties of a pyridine versus isoquinoline-based carrier group. Binding to calf thymus DNA was similar for both compounds but the distortions produced on DNA, as assessed by Tm (melting temperature) and an ethidium bromide fluorescence reporter assay, were more marked for the isoquinoline ligand. Model studies with 50-GMP (50-guanosinemonophosphate) confirmed these trends, with the product trans-[Pt(50- GMP)2(NH3)(isoquinoline)] showing evidence of restricted rotation caused by steric hinderance of three rigid planar rings on the central platinum. A cross-linking assay on pUC19 plasmid confirmed a higher % of interstrand adducts for the isoquinoline compound. This ‘‘enhanced” reactivity was matched by higher cytotoxicity in HCT116 human colon tumor cells, and also with enhanced cellular accumulation. Thus, a combination of systematic biophysical and biological studies indicates that trans-[Pt(O_2CH)_2(NH_3)(isoquinoline)] has the most promising range of chemical and biological properties for further development and examination. Published by Elsevier B.V.