期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 27, 期 18, 页码 4041-4047出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.07.027
关键词
Pyruvate carboxylase; Carboxyltransferase; alpha-Hydroxycinnamic acids; alpha-Keto acids
资金
- Marquette University Strategic Innovation Fund
Through a structure-based drug design project (SBDD), potent small molecule inhibitors of pyruvate carboxylase (PC) have been discovered. A series of alpha-keto acids (7) and alpha-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 mu M and 4.3 +/- 1.5 mu M respectively. Compound 8v is a competitive inhibitor with respect to pyruvate (K-i = 0.74 mu M) and a mixed-type inhibitor with respect to ATP, indicating that it targets the unique carboxyl-transferase (CT) domain of PC. Furthermore, compound 8v does not significantly inhibit human carbonic anhydrase II, matrix metalloproteinase-2, malate dehydrogenase or lactate dehydrogenase.
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