Synthesis and biological activity of several amino nucleoside-platinum(II) complexes.

Abstract

Several platinum(II) complexes of 3',5'-diamino-3',5'-dideoxythymidine (compound 1), 5'-amino-5'-deoxythymidine (compound 2), and 3'-amino-3'-deoxythymidine (compound 3) and the respective 2'-deoxyuridine amino nucleoside complexes, 4-6, have been synthesized. Whereas compounds 1, 2, and 4-6 had no inhibitory effect on the replication of murine L1210 cells in cell culture, compound 3 [(3'-AdThd)2PtCl2] inhibited these cells with an ED50 of 0.8 microM. Incubation of L1210 cells with 10-20 microM compound 3 for 2 h produced less than 18% inhibition of RNA, DNA, or protein synthesis, which is of questionable significance. However a 16-h incubation resulted in an increased uptake of labeled thymidine into DNA (77%), labeled uridine into RNA (17%), and labeled amino acids into protein (100%). These unexpected results indicate that inhibition of macromolecules may not be involved in the inhibition of the replication of L1210 cells. The increased incorporation of labeled metabolites into macromolecules may be related to the increase in cell volume after a 2-h incubation of L1210 cells with compound 3 plus a marked increase after 2 h in the proportion of cells in their S phase. Compound 3 appears to delay the progression of cells through their cell cycle. A marked inhibitory effect on the transport of methionine or aminoisobutyric acid into L1210 cells was found with compound 3, which was slightly greater than that produced with cisplatin. Compound 3 had a dose-dependent effect on the survival of mice bearing the L1210 ascites neoplasm, with a T/C X 100 of 175 at a dose of 320 mg/kg. Investigation of the kinetics of decomposition in aqueous systems demonstrated that the primary UV-absorbing decomposition product is 3'-amino-3'-deoxythymidine and that only a limited amount of the compound is formed (less than 8%). Although 3'-amino-3'-deoxythymidine could account for a part of the inhibition of the replication of L1210 cells in culture, it cannot account for the inhibition of amino acid transport by compound 3, the platinum complex of 3'-amino-3'-deoxythymidine. Compound 3 has been shown to limit part of the amino acid uptake into L1210 cells in a similar manner to cisplatin.