1. Cinnamic acid amides from Tribulus terrestris displaying uncompetitive α-glucosidase inhibition
- Author
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Jeong Yoon Kim, Heung Joo Yuk, Ki Hun Park, Marcus J. Curtis-Long, Keun Woo Lee, Dae Wook Kim, Yeong Hun Song, Chanin Park, and Minky Son
- Subjects
Models, Molecular ,0301 basic medicine ,Tribulus terrestris ,Tribulus ,Glycoside Hydrolase Inhibitors ,Stereochemistry ,01 natural sciences ,Cinnamic acid ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Amide ,Drug Discovery ,Structure–activity relationship ,Pharmacology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Organic Chemistry ,alpha-Glucosidases ,General Medicine ,biology.organism_classification ,Amides ,0104 chemical sciences ,Kinetics ,030104 developmental biology ,Enzyme ,chemistry ,Biochemistry ,Cinnamates ,Uncompetitive inhibitor - Abstract
The α-glucosidase inhibitory potential of Tribulus terrestris extracts has been reported but as yet the active ingredients are unknown. This study attempted to isolate the responsible metabolites and elucidate their inhibition mechanism of α-glucosidase. By fractionating T. terristris extracts, three cinnamic acid amide derivatives (1–3) were ascertained to be active components against α-glucosidase. The lead structure, N-trans-coumaroyltyramine 1, showed significant inhibition of α-glucosidase (IC50 = 0.42 μM). Moreover, all active compounds displayed uncompetitive inhibition mechanisms that have rarely been reported for α-glucosidase inhibitors. This kinetic behavior was fully demonstrated by showing a decrease of both Km and Vmax, and Kik/Kiv ratio ranging between 1.029 and 1.053. We progressed to study how chemical modifications to the lead structure 1 may impact inhibition. An α, β-unsaturation carbonyl group and hydroxyl group in A-ring of cinnamic acid amide emerged to be critical functionalities for α-glucosidase inhibition. The molecular modeling study revealed that the inhibitory activities are tightly related to π-π interaction as well as hydrogen bond interaction between enzyme and inhibitors. more...
- Published
- 2016
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