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Concise Chemoenzymatic Total Synthesis and Identification of Cellular Targets of Cepafungin I

preprint
submitted on 13.02.2020 and posted on 14.02.2020 by Alexander Amatuni, Anton Shuster, Alexander Adibekian, Hans Renata
The natural product cepafungin I was recently reported to be one of the most potent covalent inhibitors of the 20S proteasome core particle through a series of in vitro activity assays. Here, we report a short chemoenzymatic total synthesis of cepafungin I featuring the use of a regioselective enzymatic oxidation to prepare a key hydroxylated amino acid building block in a scalable fashion. The strategy developed herein enabled access to a chemoproteomic probe, which in turn revealed the exceptional selectivity and potency of cepafungin I towards the b2 and b5 subunits of the proteasome. Further structure-activity relationship studies suggest the key role of the hydroxyl group in the macrocycle and the identity of the lipid tail in modulating the potency of this natural product family. This study lays the groundwork for further medicinal chemistry exploration to fully realize the anticancer potential of cepafungin I.

Funding

Biocatalytic C -H Functionalization Logic in the Chemoenzymatic Synthesis of Therapeutic Natural Products

National Institute of General Medical Sciences

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History

Email Address of Submitting Author

hrenata@scripps.edu

Institution

The Scripps Research Institute

Country

USA

ORCID For Submitting Author

0000-0003-2468-2328

Declaration of Conflict of Interest

No conflict of interest

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