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Multi‐Functional Oxidase Activity of CYP102A1 (P450BM3) in the Oxidation of Quinolines and Tetrahydroquinolines
Author(s) -
Li Yushu,
Wong Luet L.
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201904157
Subject(s) - chemistry , aromatization , hydroxylation , quinoline , stereochemistry , combinatorial chemistry , drug discovery , mutagenesis , enzyme , small molecule , cytochrome p450 , molecule , mutant , biochemistry , organic chemistry , catalysis , gene
Tetrahydroquinoline, quinoline, and dihydroquinolinone are common core motifs in drug molecules. Screening of a 48‐variant library of the cytochrome P450 enzyme CYP102A1 (P450BM3), followed by targeted mutagenesis based on mutation‐selectivity correlations from initial hits, has enabled the hydroxylation of substituted tetrahydroquinolines, quinolines, and 3,4‐dihydro‐2‐quinolinones at most positions around the two rings in good to high yields at synthetically relevant scales (1.5 g L −1 day −1 ). Other oxidase activities, such as C−C bond desaturation, aromatization, and C−C bond formation, were also observed. The enzyme variants, with mutations at the key active site residues S72, A82, F87, I263, E267, A328, and A330, provide direct and sustainable routes to oxy‐functionalized derivatives of these building block molecules for synthesis and drug discovery.