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Intriguing generative metabolism discovery of reactive metabolite nitroso of lapatinib and relevant structural modification
Author(s) -
Huang Hong,
Bai Xue,
Yang Lijun
Publication year - 2020
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.26210
Subject(s) - chemistry , lapatinib , hydroxylation , reactive intermediate , morpholine , stereochemistry , metabolite , amine gas treating , adme , biochemistry , enzyme , medicinal chemistry , organic chemistry , cancer , biology , genetics , trastuzumab , breast cancer , in vitro , catalysis
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.