Handles for complexity building

Now, as they report in Chem, Bortz, Bennett and Fasan leverage a cytochrome P450 site-selective C–H oxyfunctionalization as the key step to install functional groups as handles for directing chemical transformations of the scaffold, generating a library of complex small molecules, through a chemoenzymatic DOS (ceDOS) strategy.

The team used variants of fatty acid hydroxylase P450_BM3, which were previously engineered for the regio- and stereoselective transformations of the sesquiterpene lactone parthenolide (PTL), a model target substrate that has anti-cancer and anti-inflammatory activity, into 9(S)-hydroxy-PTL, 14-hydroxy-PTL, and 1,10-epoxy-PTL. The stereoselectively installed functional groups were treated as chemical handles enabling diversity-generating transformations of PTL via, but not limited to, acid-catalysed rearrangements and (macro)cyclizations, ring-opening or -closing metathesis reactions, oxidations and esterifications, 1,4-additions and Diels–Alder cycloadditions on installed dienophiles. Overall, this structural diversification effort led to a library of 51 compounds. Chemoinformatic tools confirmed the elevated degree of diversity and complexity of the library, which encompasses a chemical space larger than that achievable with more common late-stage C–H functionalization strategies. Additionally, proof-of-principle assays showed a range of biological activities against cancer cell lines.