Document Type

Article

Language

eng

Publication Date

9-2019

Publisher

Elsevier

Source Publication

Bioorganic & Medicinal Chemistry

Source ISSN

0968-0896

Abstract

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.

Comments

Accepted version. Bioorganic & Medicinal Chemistry, Vol. 27, No. 18 (September 2019): 4041-4047. DOI. © 2019 Elsevier. Used with permission.

Available for download on Wednesday, September 01, 2021

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