Is reduction required for antitumour activity of platinum(IV) compounds?: Characterisation of a platinum(IV)-nucleotide adduct [enPt(OCOCH3)3(5′-GMP)] by NMR spectroscopy and ESI-MS

It is widely acknowledged that DNA is the major target of platinum based antitumour chemotherapy. During the last few years a series of kinetically inert platinum(IV) complexes has been synthesised with respect to an oral administration, to broaden the spectrum of activity and to reduce the toxic side effects. In this context the mode of action of the before mentioned anticancer compounds is of great interest. The present study wants to answer the question if direct interactions of platinum(IV) complexes with nucleotides are possible and how they can be investigated. For this purpose, a platinum(IV) complex, [enPt(OCOCH3)(4)] was reacted with guanosine-5'-monophosphate at 37 degrees C. It was shown by H-1 and N-15,H-1-ge-HMQC NMR spectroscopy that platinum(IV)-5'-GMP species were formed. They were stable over a long period without detecting any platinum(II) species. The time dependent attack of the nucleotide could be followed in a very sensitive way by the release of the acetato ligand. The adduct formed was identified as [enPt(OCOCH3)(3)(5'-GMP)] by ESI-MS. After 8 weeks sodium ascorbate was added showing that both the intact [enPt(OCOCH3)(4)] complex and the platinum(IV)-5'-GMP species had been reduced. (C) 2000 Elsevier Science S.A. All rights reserved.