Synthesis and antitumor activity of cyclotriphosphazene-(diamine)platinum(II) conjugates

Abstract

A new class of water-soluble cyclotriphosphazene-(diamine)platinum(II) conjugate drugs [NP(Am . Li-2)(Am . PtA(2))](3) (Am: dicarboxylic amino acid; AP: diamine) has been synthesized and characterized by means of elemental analysis, multinuclear (H-1, P-31, C-13, Pt-195) NMR and IR spectroscopies. All the title compounds were subjected to both in vitro and in vivo assays against the murine leukemia L1210 cell line and selected human tumor cells. Most of the title compounds have shown higher in vivo antitumor activity than cisplatin and carboplatin, and, in particular, [NP(L-Glu . Li-2)(L-Glu . Pt(-dach)](3) (Glu=glutamate, dach=trans(+/-)-1,2-diaminocyclohexane) showed extraordinary high activity (ILS>500%) equally against both parent and cisplatin-resistant leukemia L1210 cell lines. Furthermore, this candidate compound (KI 60606) exhibited a wider spectrum of in vitro activity by showing higher cytotoxicity against all the selected human tumor cells than cisplatin and, therefore, was subjected to preclinical studies which are now near completion. [(C) 2000 Lippincott Williams & Wilkins].