Oxygenating Biocatalysts for Hydroxyl Functionalisation in Drug Discovery and Development

Abstract

CÀ H oxyfunctionalisation remains a distinct challenge for synthetic organic chemists. Oxygenases and peroxygenases (grouped here as "oxygenating biocatalysts") catalyse the oxidation of a substrate with molecular oxygen or hydrogen peroxide as oxidant. The application of oxygenating biocatalysts in organic synthesis has dramatically increased over the last decade, producing complex compounds with potential uses in the pharmaceutical industry. This review will focus on hydroxyl functionalisation using oxygenating biocatalysts as a tool for drug discovery and development. Established oxygenating biocatalysts, such as cytochrome P450s and flavin-dependent monooxygenases, have widely been adopted for this purpose, but can suffer from low activity, instability or limited substrate scope. Therefore, emerging oxygenating biocatalysts which offer an alternative will also be covered, as well as considering the ways in which these hydroxylation biotransformations can be applied in drug discovery and development, such as latestage functionalisation (LSF) and in biocatalytic cascades.

Asymmetric Bio‐epoxidation of Unactivated Alkenes

“…Cytochrome P450 monooxygenase belongs to the hemethiolate protein superfamily, which are widely distributed in animals, plants, and microorganisms. [48][49][50][51] P450s catalyze the reductive activation of molecular oxygen, using the heme-iron porphyrin center to transfer one oxygen atom from molecular oxygen to organic molecules (Scheme 3) . [52] Although naturally derived P450 monooxygenases are less selective as epoxidation catalysts, their catalytic activity and selectivity can be improved by protein engineering techniques, and can even realize the oxidation reaction of various substrates, thus becoming an important supplementary strategy to chemical transformation.…”

“…Miura and Fulco first reported that Bacillus megaterium extracts have mono-oxidative effects on fatty acids. [48,49,53] The enzyme was isolated, purified, cloned and sequenced and found that the enzyme is a 120 kDa fusion protein composed of class II cytochrome P450 and NADPH-P450 reductase, and is named cytochrome P450 BM3 . [53] Cytochrome P450 BM3 was the first enzyme used to catalyze the epoxidation of unsaturated fatty acids and has been extensively studied by chemists for decades.…”

“…Cytochrome P450 monooxygenase belongs to the heme‐thiolate protein superfamily, which are widely distributed in animals, plants, and microorganisms [48–51] . P450s catalyze the reductive activation of molecular oxygen, using the heme‐iron porphyrin center to transfer one oxygen atom from molecular oxygen to organic molecules (Scheme 3) [52] .…”

Predictive Minisci and P450 Late Stage Functionalization with Transfer Learning

“…S1-S4), however the top model's performance was unable to break the 0.5 F-score barrier (Figure 2B). Evaluation of the predictions revealed that the model seemed to be especially challenged with extended conjugated systems, such as those present in loratadine (2) and imatinib (5). We hypothesized that this was due to the difficulty of atoms in one hemisphere of the molecule "seeing" atoms on the other hemisphere in the MPNN.…”

“…[1] However, methyl groups are not the only motif that can radically change pharmacological properties. Fluoro, [2] chloro, [3] trifluoromethyl, [4] and hydroxyl groups [5] are known beneficial motifs and/or functional handles in…”