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

Abstract：

: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 toward the β2 and β5 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.

journal_name

Cell Chem Biol

journal_title

Cell chemical biology

authors

Amatuni A,Shuster A,Adibekian A,Renata H

doi

10.1016/j.chembiol.2020.07.012

subject

Has Abstract

pub_date

2020-10-15 00:00:00

pages

1318-1326.e18

issue

10

eissn

2451-9456

issn

2451-9448

pii

S2451-9456(20)30285-3

journal_volume

27

pub_type

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