Evaluation of α-hydroxycinnamic Acids as Pyruvate Carboxylase Inhibitors

Authors

Daniel J. Burkett, Marquette University
Brittney N. Wyatt, Marquette University
Mallory Mews, Marquette University
Anson Bautista, Marquette University
Ryan Engel, Marquette University
Chris Dockendorff, Marquette UniversityFollow
William A. Donaldson, Marquette UniversityFollow
Martin St. Maurice, Marquette UniversityFollow

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 (K_i = 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.

Recommended Citation

Burkett, Daniel J.; Wyatt, Brittney N.; Mews, Mallory; Bautista, Anson; Engel, Ryan; Dockendorff, Chris; Donaldson, William A.; and St. Maurice, Martin, "Evaluation of α-hydroxycinnamic Acids as Pyruvate Carboxylase Inhibitors" (2019). Chemistry Faculty Research and Publications. 1001.
https://epublications.marquette.edu/chem_fac/1001