Open AccessAn Enantiodefined Conformationally Constrained Fatty Acid Mimetic and Potent Inhibitor of ToxT
Author(s) -
Lauren Markham,
Jessica D. Tolbert,
F. Jon Kull,
Charles R. Midgett,
Glenn C. Micalizio
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00378
Subject(s) - stereocenter , stereoselectivity , chemistry , virulence , regulator , vibrio cholerae , combinatorial chemistry , cholera toxin , biochemistry , stereochemistry , fatty acid , gene , computational biology , microbiology and biotechnology , bacteria , biology , genetics , enantioselective synthesis , catalysis
The chiral conformation that palmitoleic acid takes when it is bound to ToxT, the master regulator of virulence genes in the bacterial pathogen Vibrio cholerae , was used as inspiration to design a novel class of fatty acid mimetics. The best mimetic, based on a chiral hydrindane, was found to be a potent inhibitor of this target. The synthetic chemistry that enabled these studies was based on the sequential use of a stereoselective annulative cross-coupling reaction and dissolving metal reduction to establish the C13 and C9 stereocenters, respectively.