trans-Platinum(iv) pro-drugs that exhibit unusual resistance to reduction by endogenous reductants and blood serum but are rapidly activated inside cells:¹H NMR and XANES spectroscopy study

Recent results have confirmed that protection of transplatin from reactions on the path to cancer cells substantially increases their activity, suggesting that such complexes have greater potential than previously thought. In this study we have investigated the use of the platinum(iv) oxidation state and the tetracarboxylate coordination sphere to determine whether these features could impart the same stability totrans-diammineplatinum complexes that they do tocis-diam(m)ineplatinum complexes. Theciscomplexes exhibit resistance to reduction byl-ascorbate and human blood serum, but are readily reduced inside cancer cells. Studies of reduction monitored by¹H NMR revealed that oxidation oftrans-diammineplatinum(ii) complexes does not always result in significant stabilisation, but the complexestrans, trans, trans-[Pt(OAc)₄(NH₃)₂] (OAc = acetate) andtrans, trans, trans-[Pt(OPr)₂(OAc)₂(NH₃)₂] (OPr = propionate) exhibit second order half-lives of 33 h and 5.9 days respectively in the presence of a ten-fold excess ofl-ascorbate. XANES spectroscopy studies of reduction in blood models showed thattrans, trans, trans-[Pt(OAc)₄(NH₃)₂] is stable in blood serum for at least 24 hours, but is reduced rapidly in whole blood and was observed to have a half-life of approximately 4 hours in DLD-1 colon cancer cells. Consequently, the tetracarboxylatoplatinum(iv) moiety has the properties required to enable the delivery oftrans-diammine platinum complexes to cancer cells.