New Synthetic Analogs of Nitrogen Mustard DNA Interstrand Cross-Links and Their Use to Study Lesion Bypass by DNA Polymerases,Chemical Research in Toxicology

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New Synthetic Analogs of Nitrogen Mustard DNA Interstrand Cross-Links and Their Use to Study Lesion Bypass by DNA Polymerases
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2021-06-16 , DOI: 10.1021/acs.chemrestox.1c00123
Young K Cheun ₁ , Arnold S Groehler ₁ , Orlando D Schärer _{1,

2}

Affiliation

Nitrogen mustards are a widely used class of antitumor agents that exert their cytotoxic effects through the formation of DNA interstrand cross-links (ICLs). Despite being among the first antitumor agents used, the biological responses to NM ICLs remain only partially understood. We have previously reported the generation of NM ICL mimics by incorporation of ICL precursors into DNA using solid-phase synthesis at defined positions, followed by a double reductive amination reaction. However, the structure of these mimics deviated from the native NM ICLs. Using further development of our approach, we report a new class of NM ICL mimics that only differ from their native counterpart by substitution of dG with 7-deaza-dG at the ICL. Importantly, this approach allows for the synthesis of diverse NM ICLs, illustrated here with a mimic of the adduct formed by chlorambucil. We used the newly generated ICLs in reactions with replicative and translesion synthesis DNA polymerase to demonstrate their stability and utility for functional studies. These new NM ICLs will allow for the further characterization of the biological responses to this important class of antitumor agents.

中文翻译：

氮芥 DNA 链间交联的新合成类似物及其用于研究 DNA 聚合酶损伤旁路的用途

氮芥是一类广泛使用的抗肿瘤药物，通过形成 DNA 链间交联 (ICL) 发挥细胞毒性作用。尽管 NM ICL 是最早使用的抗肿瘤药物之一，但其生物学反应仍只得到部分了解。我们之前报道过通过在指定位置固相合成将 ICL 前体掺入 DNA，然后进行双还原胺化反应来生成 NM ICL 模拟物。然而，这些模拟物的结构与天然 NM ICL 不同。通过进一步发展我们的方法，我们报告了一类新的 NM ICL 模拟物，其与天然对应物的不同之处仅在于在 ICL 处用 7-deaza-dG 替换 dG。重要的是，这种方法允许合成不同的 NM ICL，此处用苯丁酸氮芥形成的加合物的模拟物进行说明。我们使用新生成的 ICL 与复制和跨损伤合成 DNA 聚合酶进行反应，以证明其稳定性和功能研究的实用性。这些新的 NM ICL 将允许进一步表征对这一类重要的抗肿瘤药物的生物反应。

更新日期：2021-07-19

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