Abstract Promutagenic O6-alkylguanine adducts in DNA are repaired in humans by O6-methylguanine-DNA-methyltransferase (MGMT) in an irreversible reaction. Here we describe the synthesis of a phosphoramidite that allows the preparation of oligodeoxyribonucleotides (ODNs) containing a novel tricyclic thio analogue of O6-methylguanine in which the third ring bridges the 6-thio group and C7 of a 7-deazapurine. These ODNs are very poor substrates for MGMT and poorly recognised by the alkyltransferase-like protein, Atl1. Examination of the active sites of both MGMT and Atl1 suggest large steric clashes hindering binding of the analogue. Such analogues, if mutagenic, are likely to be highly toxic.

中文翻译：

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含 O6-甲基鸟嘌呤三环硫代类似物的寡脱氧核糖核苷酸的合成及其被 MGMT 和 Atl1 的识别

摘要 DNA 中的促突变 O6-烷基鸟嘌呤加合物在人体中由 O6-甲基鸟嘌呤-DNA-甲基转移酶 (MGMT) 在不可逆反应中修复。在这里，我们描述了亚磷酰胺的合成，它允许制备含有 O6-甲基鸟嘌呤的新型三环硫代类似物的寡脱氧核糖核苷酸 (ODN)，其中第三个环桥接 7-脱氮嘌呤的 6-硫基和 C7。这些 ODN 是 MGMT 的非常差的底物，并且很难被烷基转移酶样蛋白 Atl1 识别。MGMT 和 Atl1 的活性位点的检查表明阻碍类似物结合的大空间冲突。此类类似物如果具有致突变性，则可能是剧毒的。