CIS-TRANS ISOMERIZATION OF [PT(L-METHIONINE)2] - METABOLITE OF THE ANTICANCER DRUG CISPLATIN

[Pt(L-Met-S,N)2] is a metabolite of the anticancer drug cis-[PtCl2(NH3 )2] (cisplatin). We have discovered that it undergoes facile cis-trans isomerization in aqueous solution, and this has been investigated by reverse-phase HPLC, H-1, N-15, and 2D [H-1, N-15] heteronuclear multip le quantum coherence (HMQC, using N-15-labeled L-HMet) NMR, CD, and UV spectroscopy. The isomerization reactions are very slow (cis --> tran s k(ct) 0.86 X 10(-5) s-1, trans --> cis, k(tc) 6.0 X 10(-5) s-1, 310 K), with the cis isomer predominating at equilibrium (K 7.0). The tran s to cis isomerization appears to be entropy-driven. Molecular modelin g and energy calculations (EHMO) for the three diastereomers of each g eometrical isomer were carried out. The passage of the isomers through membranes and their excretion from the body are discussed in terms of the distribution of charge in the isomers and their hydration.