Mitomycin C (MC), a potent antitumor drug, and decarbamoylmitomycin C (DMC), a derivative lacking the carbamoyl group, form highly cytotoxic DNA interstrand crosslinks. The major interstrand crosslink formed by DMC is the C1'' epimer of the major crosslink formed by MC. The molecular basis for the stereochemical configuration exhibited by DMC was investigated using biomimetic synthesis. The formation of DNA-DNA crosslinks by DMC is diastereospecific and diastereodivergent: Only the 1''S-diastereomer of the initially formed monoadduct can form crosslinks at GpC sequences, and only the 1''R-diastereomer of the monoadduct can form crosslinks at CpG sequences. We also show that CpG and GpC sequences react with divergent diastereoselectivity in the first alkylation step: 1"S stereochemistry is favored at GpC sequences and 1''R stereochemistry is favored at CpG sequences. Therefore, the first alkylation step results, at each sequence, in the selective formation of the diastereomer able to generate an interstrand DNA-DNA crosslink after the "second arm" alkylation. Examination of the known DNA adduct pattern obtained after treatment of cancer cell cultures with DMC indicates that the GpC sequence is the major target for the formation of DNA-DNA crosslinks in vivo by this drug.

中文翻译：

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Decarbamoylmitomycin C 进行 DNA 的序列依赖性非对映特异性和非对映发散交联。

丝裂霉素 C (MC) 是一种有效的抗肿瘤药物，而去氨甲酰丝裂霉素 C (DMC) 是一种缺乏氨基甲酰基的衍生物，可形成高细胞毒性的 DNA 链间交联。DMC形成的主要链间交联是MC形成的主要交联的C1''差向异构体。使用仿生合成研究了 DMC 所表现出的立体化学构型的分子基础。DMC形成的DNA-DNA交联是非对映特异性和非对映发散的：只有最初形成的单加合物的1''S-非对映体可以在GpC序列处形成交联，并且只有单加合物的1''R-非对映体可以在GpC序列处形成交联。 CpG 序列。我们还表明，CpG 和 GpC 序列在第一个烷基化步骤中以不同的非对映选择性进行反应：GpC 序列有利于 1"S 立体化学，CpG 序列有利于 1''R 立体化学。因此，每个序列的第一个烷基化步骤结果, 在非对映异构体的选择性形成中能够在“第二臂”烷基化后产生链间 DNA-DNA 交联。用 DMC 处理癌细胞培养物后获得的已知 DNA 加合物模式的检查表明 GpC 序列是主要目标用于通过该药物在体内形成 DNA-DNA 交联。