Back to the list of abstracts
Speciation 98: Abstracts
Nicole A. Kratochwil1, Zijian Guo1, Andrei I. Ivanov1, John A. Parkinson1, Marina Patriarca1, Piedad del Socorro Murdoch1, Patrick J. Bednarski2 and Peter J. Sadler1
1 Department of Chemistry, The
University of Edinburgh, King's Building, West Mains Road, Edinburgh
EH9 3JJ, U.K.;
2 Institut für
Pharmazie, Universität Regensburg, 93040 Regensburg, Germany
Thiols play an important role in the (de)toxification of xeniobiotics. Pt(II) complexes are thought to be inactivated by substitution reactions forming S-bridged Pt species, which are then exported from the cell. On the other hand, Pt(IV) must first be reduced in vivo by biological reductants to Pt(II) in order to exert its antitumor activity. Thus, a sensitive balance between the activation and inactivation of Pt(IV) complexes exists in biological systems. In this regard, biological thiols, in particular serum albumin and glutathione (GSH), probably play critical roles in the activation of Pt(IV) complexes. However, there is only scant information in the literature concerning the mechanism of reduction of antitumor Pt(IV) diamines by biologically important thiols. We studied the reduction of the anticancer complex trans,cis-[Pt(en)(OH)2I2] by glutathione, L-cysteine, N-acetyl-L-cysteine and serum albumin by 1H and 2D [1H, 15N] HSQC NMR spectroscopy. This work has revealed unexpected pathways of reduction and novel intermediates which may play an important role in the biological mechanism of action. It is clear that reduction of Pt(IV) prodrugs does not merely give rise to square-planar Pt(II) analogues by removal of the axial ligands, and this has implications for the design of new drugs.
