The synthesis of a series of platinum complexes of trans coordination geometry [centered around the general formula, trans-ammine(amine)dichlorodihydroxoplatinum(IV) plus corresponding tetrachloroplatinum(IV) or Pt(II) counterparts] is described as part of a drug discovery program to identify more effective platinum-based anticancer drugs, particularly targeted toward the circumvention of resistance to cisplatin. Complexes have been evaluated for antitumor activity using in vitro and in vivo tumor models. In vitro against a panel of cisplatin-sensitive and -resistant human tumor cell lines (predominantly ovarian), many of the trans platinum complexes studied (e.g., 1, R = cyclohexyl) exhibited comparable potency to cisplatin and also overcame acquired cisplatin resistance, where resistance was due mainly to either reduced drug uptake or enhanced platinum-DNA adduct removal. Moreover, 14 trans complexes showed significant in vivo antitumor activity against the subcutaneous murine ADJ/PC6 plasmacytoma model; all were platinum(IV) complexes, 13/14 possessing axial hydroxo ligands the other possessing axial ethylcarbamato ligands. Where tested, all of their respective platinum(II) or tetrachloroplatinum(IV) counterparts were inactive. Notably, three dihydroxoPt(IV) complexes (18, 29, 34) (R = c-hexyl, c-heptyl, and 1-adamantyl) retained some efficacy against a cisplatin-resistant variant of the ADJ/PC6. Compounds 18 (trans-[PtCl2(OH)2NH3-(RNH2)]) R = c-C6H11, 22, R = Me3C, 27, R = n-C6H13, 28, R = PhCH2, and 36 (trans-[PtBr2(OH)2NH3(c-C6H11NH2)]) also produced evidence of antitumor activity (> 5 days growth delay) against subcutaneously grown advanced stage human ovarian carcinoma xenografts. These data demonstrate that a series of trans-ammine(amine)dichlorodihydroxoplatinum(IV) complexes are active in vivo against both murine and human subcutaneous tumor models and represent potential leads to a new generation of platinum-based anticancer drug.

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Heteropolyoxotungstates of the Keggin class containing different heteroatoms were tested for inhibition of two strains of human immunodeficiency virus 1 (HIV-1); they exhibited varying antiviral activity. Compounds containing boron were inactive, only one of those containing phosphorus showed selective anti-viral activity, whereas all silicon-containing compounds exhibited significant anti-viral activity in C8166 cells infected with the IIIB strain. Their effectiveness was some 10-fold higher in JM cells with selectivity indices of about 2000. The silicotungstates were effective inhibitors of HIV reverse transcriptase, showing greater inhibition with RNA/DNA template primers than with DNA/DNA template.primer. Kinetic analysis demonstrated that they inhibit the enzyme by different mechanisms, as, of the four compounds examined, two competed with template.primer and two competed with deoxynucleoside triphosphate. Inhibition of DNA polymerase activity by these compounds was compared using polymerases from different sources, including human; although not necessarily most specific for HIV-1 reverse transcriptase, they did not inhibit all DNA polymerases to a similar degree.

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