Surprising reactions of iodo Pt(IV) and Pt(II) complexes with human albumin: Detection of Cys34 sulfenic acid

cis-[PtCl2(NH3)(2)] is the anticancer drug cisplatin, but the iodide analog ue cis-[PtI2(NH3)(2)] is inactive. This inactivity is usually attributed to the greater stability and lower reactivity of Pt-I bonds compared to Pt-Cl in aqueous solution. Interest in reactions of Pt(IV) complexes with thiols arises from the reductive activation of Pt(IV) anticancer drugs in blood p lasma. Recently, we found (J. Am. Chem. Sec. 1998, 120, 8253-8254) that low M-r thiols react with Pt(IV)-I bonds of trans,cis-[Pt(en)(OH)(2)I-2] via a ttack on the coordinated iodo ligand giving rise to reactive chelate-ring-o pened Pt(II) ethylenediamine species. Here we report reactions of the Pt(II ) and Pt(IV) complexes [Pt(en)I-2] and trans,cis-[Pt(en)(OH)(2)I-2] With th e major thiol in blood plasma, Cys34 of the protein albumin (66 kDa). Unexp ectedly, [Pt(en)I-2] reacted more rapidly with albumin than the cisplatin a nalogue, [Pt(en)Cl-2], and did not give products with Pt bound to Cys34. Th e Pt(IV) chloro analogue, trans,cis-[Pt(en)(OH)(2)Cl-2], did not react at a ll with albumin. Reactions of trans,cis[Pt(en)(OH)(2)I-2] with the protein, via direct attack of an iodo ligand on Cys34, gave rise to a relatively st able sulfenic acid derivative, in contrast to reactions with low M-r thiols . Reactions of Pt complexes with thiols in proteins can therefore take a di fferent course: albumin can exert control over the reactivity of Cys34 and stabilize activated derivatives such as the sulfenyl iodide and sulfenic ac id. The reactivity of iodide ligands in Pt complexes is much higher than ha s been previously recognized, and it may be possible to incorporate them in to drug design strategies.