Department of Chemistry, University of Surrey, Guildford GU2 7XH, UK.
Department of Nutritional Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK.
Bioorg Med Chem. 2020 Jun 1;28(11):115507. doi: 10.1016/j.bmc.2020.115507. Epub 2020 Apr 15.
The DNA repair enzyme AAG has been shown in mice to promote tissue necrosis in response to ischaemic reperfusion or treatment with alkylating agents. A chemical probe inhibitor is required for investigations of the biological mechanism causing this phenomenon and as a lead for drugs that are potentially protective against tissue damage from organ failure and transplantation, and alkylative chemotherapy. Herein, we describe the rationale behind the choice of arylmethylpyrrolidines as appropriate aza-nucleoside mimics for an inhibitor followed by their synthesis and the first use of a microplate-based assay for quantification of their inhibition of AAG. We finally report the discovery of an imidazol-4-ylmethylpyrrolidine as a fragment-sized, weak inhibitor of AAG.
DNA 修复酶 AAG 已在小鼠中被证明可促进组织坏死，以响应缺血再灌注或烷化剂治疗。化学探针抑制剂是研究导致这种现象的生物学机制以及作为潜在保护药物的先导，这些药物可预防器官衰竭和移植以及烷化化疗引起的组织损伤。在此，我们描述了选择芳基甲基吡咯烷作为合适的氮杂核苷类似物抑制剂的原理，然后描述了它们的合成以及首次使用基于微孔板的测定法来定量测定它们对 AAG 的抑制作用。最后，我们报告了发现咪唑-4-基甲基吡咯烷是 AAG 的片段大小的弱抑制剂。
