REACTION OF A PLATINUM(IV) COMPLEX WITH NATIVE CD,ZN-METALLOTHIONEIN IN-VITRO

The first observation of a redox process following a substitution reac tion between a platinum(IV) complex K2PtCl6 with rabbit liver native C d,Zn-MT is presented. The reaction features and products are studied b y UV-visible and circular dichroism spectroscopy, chromatography, and X-ray photoelectron spectroscopic measurements. It is a significant co mplicated reaction comprising redox and substitution reactions. The re action generates monomeric and dimeric products, and higher oligomers precipitate with intra- or intra- and intermolecular CyS-SCy linkages. Pt(IV) is reduced to Pt(II), which then binds to the monomeric and di meric products, and may also bind to higher oligomers. The beta-cluste r is more reactive than the alpha-cluster, and reacts first with K2PtC l6. Cd5Pt2 and Cd4Pt4 were found when native Cd,Zn-MT reacted with 2 a nd 4 molar equivalents of Pt(IV) for 2 h in which four Cd ions were lo cated in the alpha-cluster. The amounts of Cd and Pt ions decreased in both monomeric and dimeric products when the reaction was prolonged a nd intramolecular CyS-SCy linkages increased. Besides the oligomers wh ich precipitated, only dimeric products were formed when the reaction molar ratio of Pt(IV) to MT was more than 10:1. Cd3Pt6 and Cd1Pt8 were obtained when the reaction occurred for 2 and 72 h, respectively. The structure of the clusters may exist when native Cd,Zn-MT reacts with substoichiometric quantities of K2PtCl6 (< 0.5 K2PtCl6 per MT thiolate ) for a short time (2 h), but may be partly disrupted with stoichiomet ric or excess quantities of K2PtCl6 (greater than or equal to 0.5 K2Pt Cl6 per MT thiolate) for a long time. The disruption of the cluster st ructures results in an increase of the nonbridge thiolate and an incra se of the binding sites to Pt ions. The mechanism of the antitumor act ivity and developing drug resistance of Pt(IV) complex drugs is discus sed. (C) 1997 Elsevier Science Inc.