Reactions of Model and Anticancer Active Platinum(IV/II) Complexes - A Kinetic and Mechanistic Study

Sammanfattning: In this thesis reductions of model and anticancer active Pt(IV) complexes with thiols and ascorbic acid and substitution reactions of cisplatin and model Pt(II) complexes with S-donor nucleophiles (rescue agents) have been investigated using stopped-flow and UV/VIS spectrophotometry. Glutathione (GSH) reduction of the anticancer active Pt(IV) compounds t- and c-[PtCl4(cha)(NH3)] (cha = cyclohexylamine), t-[PtCl4(thiazole)(NH3)] and c-[PtCl4(NH3)2] at 25 oC was observed to be very fast. Thiol reduction of the non-classical Pt(IV) compound t,t,t-[PtCl2(OH)2(cha)(NH3)] (JM335) at 25 oC and pH > 7 is moderately rapid while the cis isomer c,t,c-[PtCl2(OH)2(cha)(NH3)] (JM149) is not reduced. Ascorbate (Asc2-) reduction of the orally active Pt(IV) compounds c,t,c-[PtCl2(OCOCH3)2(cha)(NH3)] (JM216) and c,t,c-[PtCl2(OCOC3H7)2(cha)(NH3)] (JM221) at near neutral pH and 35 oC is relatively slow. All the electron transfer reactions follow the rate law: -d[Pt(IV)]/dt = k [Pt(IV)] [RA]tot where k denotes a pH-dependent second-order overall rate constant and [RA]tot the total concentration of reducing agent. Thiol and ascorbate reductions of the Pt(IV) complexes containing an X-PtIV-X (X = Cl, Br) axis is suggested to proceed via a halide-bridged two-electron transfer mechanism. Ascorbate reduction of JM216 and JM221, where the chlorides are co-ordinated trans to cyclohexylamine and NH3, is proposed to follow an outer-sphere mechanism. The observed reduction reactions support the assumption that anticancer active Pt(IV) compounds require reduction to their Pt(II) counterparts before binding to the pharmacological target, DNA. Among others, glutathione and ascorbic acid are assumed to be the potential reducing agents in the body. It is concluded that Pt(IV) compounds with high rates of reduction cannot be expected to display improved activity compared to their Pt(II) analogues. The chemoprotective agents diethyldithiocarbamate (DDTC), thiosulfate, thiourea, GSH, 2-mercaptoethanesulfonate (mesna), and 2-mercaptoethylamine display a comparable reactivity towards the model complex [Pt(dien)Cl]+. DDTC was observed to be the most reactive nucleophile consistent with the report that it is the only rescue agent effective when administered after cisplatin. It is suggested that the rest of the rescue agents investigated can be expected to have the same mechanism of renal protection, although their transport and tissue distribution properties could also play a role.