摘要:
使用密度泛函理论(DFT)对O6-烷基鸟嘌呤-DNA-烷基转移酶(AGT)抑制剂的硝基类前体药物在硝基还原酶(NTR)作用下的还原机理进行了研究。结果显示，在反应的六个过渡态中，生成亚硝基反应的过渡态(TS2)和生成苯胺反应的过渡态(TS5)为反应的两个控速步骤。整个还原反应过程中水参与的质子电子耦合转移在过渡态TS2和TS6降低了反应的活化能，推测水介导的质子电子耦合转移为这两步反应的优势途径。通过绘制反应势能曲线阐明了硝基芳烃类前体药物还原机理及其反应所涉及的热力学问题，为制备高效低毒的AGT抑制剂的前体药物提供理论基础。
Abstract:
The reduction mechanism of O6-Alkylguanine DNA Alkyltransferase inhibitor of the nitro group of the pro-drug in the Nitro Reductase (NTR) was studied by using the Density Functional Theory (DFT). The results showed that the transitions of TS2 (yielding nitroso compound) and TS5 (yielding aniline compound) were the rate-limiting steps among the six reaction transition states. Single water molecule-mediated proton coupled electron transfer can lower the reactive activation energy of TS2 and TS6; thus it is speculated that water-mediated proton coupled electron transfer is the optimal reaction pathway of TS2 and TS6. The reduction mechanism of the prodrug of nitro aromatic compound and the involved reaction thermodynamics can be clearly presented by the potential energy curve. This study can provide a theoretical basis for designing more efficient hypoxia-activated AGT inhibitors with less side effects.