Iyengar B S, Dorr R T, Remers W A, Kowal C D
Department of Pharmaceutical Sciences and Cancer Center, University of Arizona, Tucson 85721.
J Med Chem. 1988 Aug;31(8):1579-85. doi: 10.1021/jm00403a016.
Treatment of mitomycin C with pyrimidine nucleotides in acidic media produced derivatives of 2,7-diaminomitosene in which C-1 was covalently bound to the phosphate group of the nucleotides. On reduction, these derivatives liberated the nucleotides and a mitomycin intermediate that alkylated DNA. Their reduction in the presence of 2'-deoxyguanosine produced some bifunctional alkylation as did mitomycin C. They were readily taken up by L1210 leukemia cells, in which they showed potent cytotoxicity. These properties suggest that they are acting as prodrugs capable of conversion into two active species. The uridylate derivative showed activity comparable to that of mitomycin C against P-388 leukemia in mice.
在酸性介质中，用嘧啶核苷酸处理丝裂霉素C会产生2,7-二氨基丝裂蒽的衍生物，其中C-1与核苷酸的磷酸基团共价结合。还原后，这些衍生物释放出核苷酸和一种能使DNA烷基化的丝裂霉素中间体。在2'-脱氧鸟苷存在下对它们进行还原会产生一些双功能烷基化，丝裂霉素C也是如此。它们很容易被L1210白血病细胞摄取，在这些细胞中它们表现出强大的细胞毒性。这些特性表明它们作为前药能够转化为两种活性物质。尿苷酸衍生物对小鼠P-388白血病的活性与丝裂霉素C相当。
