2. Academic Validation
  3. Evaluation of α-hydroxycinnamic acids as pyruvate carboxylase inhibitors

Evaluation of α-hydroxycinnamic acids as pyruvate carboxylase inhibitors

  • Bioorg Med Chem. 2019 Sep 15;27(18):4041-4047. doi: 10.1016/j.bmc.2019.07.027.
Daniel J Burkett 1,  Brittney N Wyatt 2,  Mallory Mews 2,  Anson Bautista 1,  Ryan Engel 1,  Chris Dockendorff 1,  William A Donaldson 3,  Martin St Maurice 4
Affiliations

Affiliations

  • 1 Department of Chemistry, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • 2 Department of Biological Sciences, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • 3 Department of Chemistry, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881, USA. Electronic address: [email protected].
  • 4 Department of Biological Sciences, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881, USA. Electronic address: [email protected].
PMID: 31351848 DOI: 10.1016/j.bmc.2019.07.027
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.

Keywords

Carboxyltransferase; Pyruvate carboxylase; α-Hydroxycinnamic acids; α-Keto acids.

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