Late stage functionalization of lead compounds is of high interest in drug discovery since it offers an easy access to metabolites and derivatives of a lead compound without the need to redesign an often long multistep synthesis. Owing to their high degree of chemoselectivity biocatalytic transformations and enzymatic oxidations in particular are potentially very powerful since they could allow the synthesis of less lipophilic derivatives of a lead compound.<br/>It will be presented how the concept of docking/protecting groups could be used in a biomimetic fashion helping to steer the regioselectivity of a P450BM3-mediated oxidation. A novel set of docking/protecting groups was designed that can be cleaved under very mild conditions and address the often problematic aqueous solubility of the substrates. Vabicaserin was used as tool compound containing typical groups such as basic, aliphatic and aromatic moieties. The results were rationalized with the help of in silico docking and molecular dynamic studies (Chemistry – A European Journal in press).

Enzymatic late-stage oxidation of lead compounds with solubilizing biomimetic docking/protecting groups

2019 Spring National Meeting

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