A new class of water-soluble cyclotriphosphazene-(diamine)platinum(II) conjugate drugs [NP(Am-Li2)(Am.PtA2)]3 (Am: dicarboxylic amino acid; A2: diamine) has been synthesized and characterized by means of elemental analysis, multinuclear (1H, 31P, 13C, 195Pt) 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-Li2)(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.

Thermal polymerization of cyclotriphosphazenes fully substituted with 2-, 3-, and 4-pyridinoxides have been attempted both in the solid state and in solution. Among these ring-strain-free trimeric isomers, hexakis(3-pyridinoxy)cyclotriphosphazene (1) did not undergo polymerization either in the solid state or in solution, but 4-pyridinoxy (2) and 2-pyridinoxy analogues (3) have been found to undergo polymerization at 150 and 200 °C, respectively, in the absence of any catalyst. In particular, the thermal solution polymerization of 2 in 1,2,4-trichlorobenzene at 200 °C resulted in a linear polymer in 80% yield which was the same as the product obtained by a nucleophilic substitution of poly(dichlorophosphazene) with 4-pyridinoxide. DSC analysis of the trimers has shown that 2 and 3 have exothermic peaks at 179.4 and 224.1 °C, respectively, whereas 1 does not have an exothermic peak, and it has been found that the polymerizability and temperature range for polymerization of the cyclic trimers are closely related to their thermal properties: trimers having an exothermic peak are amenable to the thermal polymerization reaction, and the temperature range for polymerization can be predicted therefrom. Along with such a finding, the results of the thermal conductivity measurements of trimers 1, 2, and 3 conclusively support the cationic ring-opening mechanism. The difference in polymerizability of these trimeric isomers may be explicable in terms of an electronic difference of the substituent isomers: 4- and 2-pyridinoxide anions are more resonance stabilized than the 3-pyridinoxide anion, which probably makes a difference in the degree of ionization of the substituents from the trimeric phosphazene ring at the initial step of the ring-opening polymerization.

The melt polymerization of hexachlorocyclotriphosphazene to poly(dichlorophosphazene) has been studied in the presence of organotin (IV) compounds. Unlike other typical Lewis acids, diethyltin (IV) chloride, Et2SnCl2, has shown to be an inhibitor for the thermal polymerization of the trimer, raising the activation energy to 70 kcal/mol. Diethyltin(IV) chloride remarkably delayed the rate of polymerization and efficiently inhibited the crosslinking reaction, thus leading to an improvement in the yield of the linear polymer without sacrifice to its molecular weight. © 1993 John Wiley & Sons, Inc.

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