Mechanisms for Reduction of Model and Anticancer Active Platinum(IV) Compounds By Biological Molecules

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Electron transfer reactions of model and anticancer active platinum(IV) complexes with thiols and ascorbate ions have been investigated in a 1.0 M aqueous perchlorate medium as a function of pH and temperature using stopped-flow and conventional UV-vis spectrophotometry. Reductions of the anticancer active platinum(IV) complexes, dxms- [PtCl 4(NH3)( thiazole)] (1), /ram-[PtCl4(cha)(NH3)] (2), CM -[PtCl4(cha)(NH3)] (3), and cis- [PtCl 4(NH3)2] (4) by glutathione and of ( ram, ( vans, /ra/Ay- pPtCl2 (OH)2(cha) (NH3)] (5) (cha = cyclohexylamine) by a series of thiols have been studied at 25 °C in the regions 2.00 < pH<7.00 and 6.80 < pH < 11.22, respectively, using an Applied Photophysics Stopped-Flow spectrophotometer. Reductions of the model platinum(IV) complexes, CM-[PtCl4(NH3)2] (4 ), / ra/«-[TtCl4(NH3)2] (11), [PtCU]2' (12), [PtBr6]2" (13), /m/«-[PtCl 2(en) 2]2+ (14), and trans- [PtBr2(NH3)4]2+ (15) by ascorbate ions HAsc and Asc2' have been studied at 25 °C in the interval 1.75 < pH < 7.20 using the same stopped -flow technique. Reduction of the orally active platinum(IV) dicarboxylate compounds, cis, dans, c/.v-[PtCl2(OAc)2(cha)(NH3)] (JM216) (7) and cis, ( vans, c/A-[PtCl 2(OCOC3Hv)2(cha)(Nn3)] (JM221) (8) by ascorbate Asc2 at 35 °C in the interval 7.0 < pH < 7.5 has been investigated using a Cary 300 UV/VIS spectrophotometer. The kinetics of reduction of the geometrical isomers of compound 7, viz. dcms, cis, c/.s-[PtCl2(OAc)2(cha)(NH3)] (JM394) (9) and dans, (vans, dctns- [PtCl2(OAc)2(cha)(NH3)] (JM576) (10) by Asc2' and/or HAsc at 25 °C in the interval 4.0 < pH < 7.0 have also been studied using the stopped-flow technique in order to obtain further insight into the mechanism of reduction. The redox reactions follow the second -order rate law: -d[Pt(IV)]/d / = k [Red ]lot [Pt (IV)] where k denotes a pH-dependent second-order overall rate constant and [Red ]tot the total concentration of reductant . The stoichiometeries [Pt (IV)]:[Red] for thiol (RSH) and ascorbate (Asc) reductions are 1:2 and 1:1, respectively. Reduction of the platinum(lV) complexes containing a Cl-PtIV-Cl axis by the thiols and ascorbate ions is suggested to involve a reductive attack on one of such chlorides by thiolate/thiol or Asc2'/HAsc' leading to the formation of a chloride-bridged transition state. Ascorbate reduction of compounds 7 and 8 which have no Cl -Pt-Cl axis, on the other hand, is proposed to take place via an outer-sphere mechanism. The proposed mechanisms for reductions of the model and anticancer active platinum(IV) compounds by ascorbate appear to have not been reported previously. Reduction of compounds1- 4 by glutathione under the conditions used is very rapid while that of 5 (JM335) by the series of thiols is comparatively slow. Reduction of the oral anticancer platinum(IV) compounds 7 (JM216) and 8 (JM221) by ascorbate at the near neutral pH is more than 3 orders of magnitude slower than that of compounds 9 (JM394) and 10 (JM576). The half-life for reduction of 7 (JM216) by 5 mM total concentration of ascorbic acid (15-fold excess) at pH 7.4 and 35 °C was observed to be ca. 12 min. The deprotonated A species RS' (thiolate) and Asc ' (ascorbate) are the predominant reductants for platinum(IV) complexes in the near neutral region.