Synthesis And α-Glucosidase Inhibitory Activities Of Nphenylprophenoyl-L-Amino Acids

α-Glucosidase inhibitors can effectively control the postprandial hyperglycemia,and were used as common medicine for the type 2 diabetes mel itus. Curcumin, chalcone, phenolic acids and many other natural products with phenylpropenoyl moiety have been reported with good α-glucosidase inhibitory activities. Researches have demonstrated that the cocoa extract could well control the postprandial glucose level of diabetic rats. Considering the large family of phenolic acid amides with L-amino acid moiety present in cocoa, we speculated that they may act as α-glucosidase inhibito rs and cause hypoglycemic effects in cocoa. in this paper, N-phenylpropenoyl-L-a mino acids(NPAs) were synthesized and their inhibitory activities against α-glucosidase from Saccharomyces cerevisiae(EC 3.2.1.20) were evaluated. The content and conclusions are as follows:(1) Forty two N-phenylpropenoyl-L-amino acids were synthesized with ferulic acid, 4-methoxycinnamic acid and 4-coumaric acid as the raw materials respectively. All the synthesized compounds were confirmed by 1H NMR and LC-MS techniques.(2) The in vitro α-glucosidase inhibtory activieties were evaluated with pNPG as the substrate. The result showed that the IC50 values of the compounds ranged from 0.04 to 34.43 mM, and some were lower than that of acabose(IC50=1.70 mM), the positive control. Both the amino acids and substituents on benzene ring in the structures have effect on the acivities. In the ferulic acid and 4-methoxycinnamic acid derivatives, compounds with phenylalanine, tryptophan, serine, threonine, threonine, glutamic acid and aspartate acid moeity exhibited higher inhibition activities than the other amino acids substituted products. Derivatives with para hydroxy substituted on the benzene ring showed the highest activities, among which, compound with alanine showed much more strong activities than acarbose with IC50 values 0.004 mM, kinetic analys is indicated that it acted as a mixed-type inhibitor with Ki value of 0.0124 mM. The inhibitory acitivities of some of the compounds against mouse intestinal enzyme were investigated, the result showed that some of the compounds had good inhibitor y acitivities under the same concentration of 8 mM.(3) Three-dimensional quantitative structure-activity relationship(3D-QSAR) model for comparative molecular field analysis(CoMFA) was generated with the activity data of the compounds. The predictive capabilities of the obtained model wasvalidated. The Model parameters(q2=0.561, r2=0.977) show that the constructed model had good stability. The predicted activities of the copounds were in accordance with the observed activities, which indicated that the model had good predictive capabilit ies. The contour map generated from the model showed that bulk groups and high electron density groups on the amino acid residues were benefit to their activities, moreover, substituent with low electron density and small steric hindrance on the benzene ring were helpful to improve the activities.(4) The 3D structure of the α-glucosidase from S. cerevisiae was created by homology modeling with the the crystal ographic structure of S. cerevisiae isomaltase as the template. The docking study was run by Surflex-dock, and the results showed that the compounds could bind to one, two or all of the activec sites Asp214, Glu276 and Asp349 via hydrogen bonds and a π-π stacking with Phe157 also contributed to the binding force.