Synthesis of Mitomycin C and decarbamoylmitomycin C N6 deoxyadenosine-adducts.
Synthesis of Mitomycin C and decarbamoylmitomycin C N6 deoxyadenosine-adducts.
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DOI：
10.1016/j.bioorg.2019.103280
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发表时间：
2019
影响因子：
5.1
通讯作者：
M. Zheng;Seokjin Hwang;Timothy Snyder;Jake M Aquilina;G. Proni;M. Paz;P. Pradhan;Shu-Yuan Cheng;Elise Champeil
中科院分区：
文献类型：
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作者：
M. Zheng;Seokjin Hwang;Timothy Snyder;Jake M Aquilina;G. Proni;M. Paz;P. Pradhan;Shu-Yuan Cheng;Elise Champeil
丝裂霉素C （MC）是一种抗癌药物，它的类似物decarbamoylmitomycin C （DMC）是dna烷基化剂。MC目前用于临床，其细胞毒性主要是由于其能够形成链间交联（Interstrand交联，ICLs），阻碍DNA复制，从而阻止癌细胞增殖。然而，MC和DMC都可以用DNA生成单加合物。特别是，我们最近发现DMC和MC一样，可以与DNA形成脱氧腺苷（dA）单加合物。这些单加合物所起的生物学作用值得研究。为了探索这些加合物的作用，并在两种药物处理的培养细胞中提取的DNA的酶切中检测它们，我们需要获得参比化合物，即MC和DMC - da -单核苷加合物。以前用于生成MC和DMC单核苷加合物的仿生方法繁琐且产率很低。在这里，我们描述了MC和DMC脱氧腺苷加合物的C-1外显体的非对映特异性化学合成。合成的关键步骤是6-氟嘌呤2 ' -脱氧核糖核苷与适当保护的立体异构体三胺核苷之间的芳香取代反应，在腺嘌呤-核苷键上形成具有反或反立体化学构型的受保护mc - da加合物。基于氟化物的脱保护方法生成了最终的四种参考化合物：两种立体异构体MC-dA加合物和两种立体异构体DMC-dA加合物。本文合成的MC和DMC-dA加合物将作为检测和鉴定这两种药物处理的培养细胞DNA中形成的加合物的标准。
Mitomycin C (MC), an anti-cancer drug, and its analog, decarbamoylmitomycin C (DMC), are DNA-alkylating agents. MC is currently used in the clinics and its cytotoxicity is mainly due to its ability to form Interstrand Crosslinks (ICLs) which impede DNA replication and, thereby, block cancer cells proliferation. However, both MC and DMC are also able to generate monoadducts with DNA. In particular, we recently discovered that DMC, like MC, can form deoxyadenosine (dA) monoadducts with DNA. The biological role played by these monoadducts is worthy of investigation. To probe the role of these adducts and to detect them in enzymatic digests of DNA extracted from culture cells treated by both drugs, we need access to reference compounds i.e. MC and DMC dA-mononucleoside adducts. Previous biomimetic methods used to generate MC and DMC mononucleoside adducts are cumbersome and very low yielding. Here, we describe the diastereospecific chemical synthesis of both C-1 epimers of MC and DMC deoxyadenosine adducts. The key step of the synthesis involves an aromatic substitution reaction between a 6-fluoropurine 2′-deoxyribonucleoside and appropriately protected stereoisomeric triaminomitosenes to form protected-MC-dA adducts with either anSorRstereochemical configuration at the adenine-mitosene linkage. Fluoride-based deprotection methods generated the final four reference compounds: the two stereoisomeric MC-dA adducts and the two stereoisomeric DMC-dA adducts. The MC and DMC-dA adducts synthesized here will serve as standards for the detection and identification of such adducts formed in the DNA of culture cells treated with both drugs.