Evaluation of α-hydroxycinnamic acids as pyruvate carboxylase inhibitors

[Display omitted] Through a structure-based drug design project (SBDD), potent small molecule inhibitors of pyruvate carboxylase (PC) have been discovered. A series of α-keto acids (7) and α-hydroxycinnamic acids (8) were prepared and evaluated for inhibition of PC in two assays. The two most potent...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2019-09, Vol.27 (18), p.4041-4047
Main Authors: Burkett, Daniel J., Wyatt, Brittney N., Mews, Mallory, Bautista, Anson, Engel, Ryan, Dockendorff, Chris, Donaldson, William A., St. Maurice, Martin
Format: Article
Language:English
Subjects:
Carboxyltransferase
Pyruvate carboxylase
α-Hydroxycinnamic acids
α-Keto acids
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Summary:[Display omitted] Through a structure-based drug design project (SBDD), potent small molecule inhibitors of pyruvate carboxylase (PC) have been discovered. A series of α-keto acids (7) and α-hydroxycinnamic acids (8) were prepared and evaluated for inhibition of PC in two assays. The two most potent inhibitors were 3,3′-(1,4-phenylene)bis[2-hydroxy-2-propenoic acid] (8u) and 2-hydroxy-3-(quinoline-2-yl)propenoic acid (8v) with IC50 values of 3.0 ± 1.0 μM and 4.3 ± 1.5 μM respectively. Compound 8v is a competitive inhibitor with respect to pyruvate (Ki = 0.74 μM) and a mixed-type inhibitor with respect to ATP, indicating that it targets the unique carboxyltransferase (CT) domain of PC. Furthermore, compound 8v does not significantly inhibit human carbonic anhydrase II, matrix metalloproteinase-2, malate dehydrogenase or lactate dehydrogenase.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2019.07.027