Lapatinib is required as a therapy for advanced or metastatic breast cancer. However, its reactive metabolite (RM) nitroso was implicated in idiosyncratic hepatotoxicity. Density functional theory was performed to explore the metabolism of nitroso formation. Primary hydroxylation amine is a critical intermediate to produce nitroso. Three pathways from secondary alkylamine lapatinib to primary hydroxylation amine were designed and discussed. Calculation results show that it is difficult to form primary hydroxylation amine through common proposed hydrolysis nitrone with a barrier of 36.67 kcal/mol (path A), but it is smoothly formed by paths B and C with moderate determined barriers of 15.09 kcal/mol and 16.56 kcal/mol, respectively. Subsequently, we demonstrate that the mechanism of nitroso formation from primary hydroxylation amine should be a double hydrogen atom transfer rather than the previously proposed hydrolysis primary dihydroxylation amine. The barrier of the former is obviously lower than the latter. Based on metabolism results and structure analysis, several lapatinib derivatives are designed. Molecular docking of designed compounds with epidermal growth factor receptor (EGFR) shows that they share a similar binding mode with lapatinib. In particular, 2a to 2d show similar binding energy to lapatinib. This work showed metabolism details of nitroso formation from lapatinib and its structure modification, which can enrich the metabolism of amine drugs and provide guidance for drug optimization and design.

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拉帕替尼活性代谢物亚硝基的有趣的生成代谢发现及相关的结构修饰

拉帕替尼需要作为晚期或转移性乳腺癌的治疗方法。但是，其反应性代谢物（RM）亚硝基与特异性肝毒性有关。进行密度泛函理论研究亚硝基形成的代谢。伯羟基化胺是生产亚硝基的关键中间体。设计和讨论了从仲烷基胺拉帕替尼到伯羟基化胺的三种途径。计算结果表明，很难通过通常提出的水解硝酮以36.67 kcal / mol的势垒形成伯羟基化胺（路径A），但是它是由路径B和C平稳形成的，具有确定的15.09 kcal / mol的势垒和分别为16.56 kcal / mol。后来，我们证明由伯羟基化胺形成亚硝基的机理应该是氢原子的双重转移，而不是先前提出的水解伯二羟基化胺。前者的壁垒明显低于后者。根据代谢结果和结构分析，设计了几种拉帕替尼衍生物。设计的化合物与表皮生长因子受体（EGFR）的分子对接表明，它们与拉帕替尼具有相似的结合模式。尤其是，设计的化合物与表皮生长因子受体（EGFR）的分子对接表明，它们与拉帕替尼具有相似的结合模式。尤其是，设计的化合物与表皮生长因子受体（EGFR）的分子对接表明，它们与拉帕替尼具有相似的结合模式。尤其是，图2a至2d显示与拉帕替尼相似的结合能。这项工作显示了拉帕替尼形成亚硝基的代谢细节及其结构修饰，可以丰富胺类药物的代谢，并为药物优化和设计提供指导。