title: Cinnamic acid amides from Tribulus terrestris displaying uncompetitive α-glucosidase inhibition.
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.
authors.affiliation: Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Yeong Hun
authors.initials: YH
authors.lastname: Song
authors.affiliation: Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Dae Wook
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, United States.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Curtis-Long
authors.affiliation: Division of Applied Life Science (BK21 plus), PMBBRC, RINS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Chanin
authors.initials: C
authors.lastname: Park
authors.affiliation: Division of Applied Life Science (BK21 plus), PMBBRC, RINS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Minky
authors.initials: M
authors.lastname: Son
authors.affiliation: Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Jeong Yoon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Heung Joo
authors.initials: HJ
authors.lastname: Yuk
authors.affiliation: Division of Applied Life Science (BK21 plus), PMBBRC, RINS, Gyeongsang National University, Jinju 660-701, Republic of Korea. Electronic address: kwlee@gnu.ac.kr.
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju 660-701, Republic of Korea. Electronic address: khpark@gnu.ac.kr.
authors.forename: Ki Hun
authors.initials: KH
authors.lastname: Park
mesh_terms: D000577:Amides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002934:Cinnamates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D065089:Glycoside Hydrolase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D032444:Tribulus / Q000737:chemistry*; D000520:alpha-Glucosidases / Q000378:metabolism*
chemical_list: D000577:Amides; D002934:Cinnamates; D065089:Glycoside Hydrolase Inhibitors; C029010:cinnamic acid; D000520:alpha-Glucosidases
keywords: Cinnamic acid amide; Molecular docking; Tribulus terrestris; Uncompetitive inhibition; α-Glucosidase