Multi‐functional oxidase activity of CYP102A1 (P450BM3) in the oxidation of quinolines and tetrahydroquinolines

Journal article

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/day). Other oxidase activities such as C-C bond desaturation, aromatisation 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-functionalised derivatives of these building block molecules for synthesis and drug discovery.

Authors: Li, Y; Wong, LL

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Angewandte Chemie International Edition
• Volume: 58
• Issue: 28
• Pages: 9551-9555
• Publication date: 2019-05-28
• Acceptance date: 2019-05-15
• DOI: 10.1002/anie.201904157
• EISSN: 1521-3773
• ISSN: 1433-7851
• Pmid: 31094046
• Language: English
• Keywords: nitrogen heterocycles; alkaloids; P450; C-H activation; protein engineering; FFR