Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 58, Issue 28, Pages 9551-9555Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201904157
Keywords
alkaloids; C-H activation; nitrogen heterocycles; P450; protein engineering
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Funding
- Oxford University
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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 (1.5gL(-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.
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