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  • Title: Relationships between reduction properties and cancer cell growth inhibitory activities of cis-dichloro- and cis-diiodo-Pt(IV)-ethylenediamines.
    Author: Kratochwil NA, Bednarski PJ.
    Journal: Arch Pharm (Weinheim); 1999 Aug; 332(8):279-85. PubMed ID: 10489538.
    Abstract:
    The chemical reactivities and cancer cell growth inhibitory activities of a new series of cis-diiodo-Pt(IV)-ethylenediamines were compared and contrasted with their cis-dichloro-Pt(IV)-counterparts, cis-Diiodo-Pt(IV)-ethylenediamines bearing various axial ligands (i.e., OH, OAc, OCOCF3, OSO2CH3) were prepared by oxidizing [PtI2(en)] with 30% H2O2 to yield trans,cis-[PtOH2I2(en)], which was then reacted with either Ac2O, (CF3CO)2O, or (SO2CH3)2O in CH2Cl2. The cis-diiodo-Pt(IV) complexes were readily reduced by biological thiols such as L-cysteine, glutathione (GSH), and bovine serum albumin (BSA) at pH 6.9 and 37 degrees C; the kinetics of reduction were second-order with respect to thiol concentration. In contrast, the cis-dichloro analogues were stable in the presence of GSH. The reduction potentials estimated by means of cyclovoltammetry for the Pt(IV) complexes are useful for obtaining a ranking order of reactivity towards biological thiols; however, the reduction potentials alone cannot be used to predict whether a Pt(IV) complex will be reduced by GSH at biologically relevant concentrations. GSH greatly facilitated the platination of calf thymus DNA by the diiodo-Pt(IV) complexes, which was > 90% complete after 24 h at 37 degrees C when the ratio of GSH to Pt(IV) was 2:1. DNA-platination by trans,cis-[Pt(OH)2I2(en)] and trans,cis-[Pt(OAc)2I2(en)] were dependent on the presence of GSH while trans,cis-[Pt(OSO2CH3)2I2(en)] showed 23% DNA platination after 24 h in the absence of GSH. In contrast, the dichloro analogues trans,cis-[Pt(OH)2Cl2(en)] and trans,cis-[Pt(OAc)2Cl2(en)] failed to react with DNA in the presence of either low (0.015 mM) to high (3.0 mM) concentrations of GSH. Cell culture experiments with four human cancer cell lines showed that the maximal growth inhibitory activity of the cis-diiodo-Pt(IV)-ethylenediamines was reached within a 24 h exposure to platinum complex, while the dichloro-Pt(IV) analogues required a much longer drug-exposure time (i.e., 96 h) to reach maximal activity.
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