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Int. J. Mol. Sci. 2016, 17(10), 1656; doi:10.3390/ijms17101656

Cinnamide Derivatives as Mammalian Arginase Inhibitors: Synthesis, Biological Evaluation and Molecular Docking

1
PEPITE EA4267, University Bourgogne Franche-Comté, F-25000 Besançon, France
2
University Lille, EA 7394-ICV-Institut Charles Viollette, F-59000 Lille, France
3
Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, 41 Dinh Tien Hoang, Dist 1, Ho Chi Minh City 700000, Vietnam
*
Author to whom correspondence should be addressed.
Academic Editor: Alejandro Cifuentes
Received: 22 July 2016 / Revised: 22 September 2016 / Accepted: 23 September 2016 / Published: 29 September 2016
(This article belongs to the Section Bioactives and Nutraceuticals)
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Abstract

Arginases are enzymes that are involved in many human diseases and have been targeted for new treatments. Here a series of cinnamides was designed, synthesized and evaluated in vitro and in silico for their inhibitory activity against mammalian arginase. Using a microassay on purified liver bovine arginase (b-ARG I), (E)-N-(2-phenylethyl)-3,4-dihydroxycinnamide, also named caffeic acid phenylamide (CAPA), was shown to be slightly more active than our natural reference inhibitor, chlorogenic acid (IC50 = 6.9 ± 1.3 and 10.6 ± 1.6 µM, respectively) but it remained less active that the synthetic reference inhibitor Nω-hydroxy-nor-l-arginine nor-NOHA (IC50 = 1.7 ± 0.2 µM). Enzyme kinetic studies showed that CAPA was a competitive inhibitor of arginase with Ki = 5.5 ± 1 µM. Whereas the activity of nor-NOHA was retained (IC50 = 5.7 ± 0.6 µM) using a human recombinant arginase I (h-ARG I), CAPA showed poorer activity (IC50 = 60.3 ± 7.8 µM). However, our study revealed that the cinnamoyl moiety and catechol function were important for inhibitory activity. Docking results on h-ARG I demonstrated that the caffeoyl moiety could penetrate into the active-site pocket of the enzyme, and the catechol function might interact with the cofactor Mn2+ and several crucial amino acid residues involved in the hydrolysis mechanism of arginase. The results of this study suggest that 3,4-dihydroxycinnamides are worth being considered as potential mammalian arginase inhibitors, and could be useful for further research on the development of new arginase inhibitors. View Full-Text
Keywords: arginase inhibitor; cinnamide; docking; screening; structure-activity relationships arginase inhibitor; cinnamide; docking; screening; structure-activity relationships
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Pham, T.-N.; Bordage, S.; Pudlo, M.; Demougeot, C.; Thai, K.-M.; Girard-Thernier, C. Cinnamide Derivatives as Mammalian Arginase Inhibitors: Synthesis, Biological Evaluation and Molecular Docking. Int. J. Mol. Sci. 2016, 17, 1656.

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