Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin C.
Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin C.
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DOI：
10.1002/chem.201802038
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发表时间：
2018-09-06
期刊：
影响因子：
--
通讯作者：
Champeil E
中科院分区：
文献类型：
--
作者：
Aguilar W;Paz MM;Vargas A;Zheng M;Cheng SY;Champeil E
丝裂霉素C（MC）是一种抗肿瘤药物，其衍生物十氨甲酰丝裂霉素C（DMC）可使DNA烷基化，形成脱氧鸟苷单加合物和链间交联（ICL）。有趣的是，在哺乳动物培养细胞中，MC主要形成在鸟嘌呤-线粒体键处具有1”-R立体化学的脱氧鸟苷加合物（1”-α），而DMC主要形成具有1”-S立体化学的加合物（1”-β）。在这里，我们提出的结果，我们的研究单烷基化DNA的DMC。结果表明，1”-β-脱氧鸟苷加合物的形成需要DMC的双功能还原活化，而单功能活化只产生1”-α-加合物。所形成的脱氧鸟苷加合物的立体化学也依赖于DNA烷基化的区域选择性和总DNA CG含量。此外，我们发现温度在丝裂霉素对双链DNA烷基化的区域选择性中起决定性作用：在0°C下，脱氧腺苷（dA）和脱氧鸟苷（dG）烷基化都发生，而在37 °C下，丝裂霉素优先烷基化dG。我们实验室开发的研究DMC-DNA烷基化的新反应方案提高了在特定位点含有DMC 1”-β-脱氧鸟苷加合物的寡核苷酸可以通过仿生方法合成的可能性。十氨甲酰丝裂霉素C（DMC）在GpC和CpG序列处形成DNA脱氧鸟苷单加合物。产生的主要脱氧鸟苷加合物在哺乳动物DNA中的每个序列处具有相反的立体化学构型。GpC序列是该药物在培养细胞中哺乳动物DNA（42% CG）的主要靶标，主要加合物在C1”处具有1”-β（顺式）立体化学。在富含CG的DNA中，有利于形成1”-α（反式）加合物。
Mitomycin C (MC), an antitumor drug, and decarbamoylmitomycin C (DMC), a derivative of MC, alkylate DNA and form deoxyguanosine monoadducts and interstrand crosslinks (ICLs). Interestingly, in mammalian culture cells, MC forms primarily deoxyguanosine adducts with a 1”-R stereochemistry at the guanine-mitosene bond (1”-α) whereas DMC forms mainly adducts with a 1”-S stereochemistry (1”-β) The molecular basis for the stereochemical configuration exhibited by DMC has been investigated using biomimetic synthesis. Here, we present the results of our studies on the monoalkylation of DNA by DMC. We show that the formation of 1”-(β-deoxyguanosine adducts requires bifunctional reductive activation of DMC, and that monofunctional activation only produces 1”-α-adducts. The stereochemistry of the deoxyguanosine adducts formed is also dependent on the regioselectivity of DNA alkylation and on the overall DNA CG content. Additionally, we found that temperature plays a determinant role in the regioselectivity of duplex DNA alkylation by mitomycins: At 0°C, both deoxyadenosine (dA) and deoxyguanosine (dG) alkylation occur whereas at 37 °C, mitomycins alkylate dG preferentially. The new reaction protocols developed in our laboratory to investigate DMC-DNA alkylation raise the possibility that oligonucleotides containing DMC 1”-β-deoxyguanosine adducts at a specific site may be synthesized by a biomimetic approach. Decarbamoylmitomycin C (DMC) forms DNA deoxyguanosine monoadducts both at GpC and CpG sequences. The major deoxyguanosine adducts produced have the opposite stereochemical configuration at each sequence in mammalian DNA. The GpC sequence is the major target for mammalian DNA (42% CG) in culture cells by this drug and the major adduct has 1”-β (cis) stereochemistry at C1”. In CG rich DNA, formation of 1”-α (trans) adduct is favored.
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