title: Voglibose-inspired synthesis of new potent α-glucosidase inhibitors N-1,3-dihydroxypropylaminocyclitols.
abstract: Voglibose, an N-1,3-dihydroxypropylaminocyclitol, has widely been used as an effective α-glucosidase inhibitor for diabetes therapy. Several attempts have been made to synthesize closely related analogues through the coupling of various aminocyclitols and propane-1,3-diol; however, most of them showed weaker or no inhibition. In this communication, we synthesized a pair of new N-1,3-dihydroxypropylaminocyclitols (10 and 11) using (+)-proto-quercitol (1) as a cyclitol core structure. The newly synthesized compounds revealed potent rat intestinal α-glucosidases, particularly against maltase, with IC50 values at submicromolar. Subsequent study on mechanisms underlying the inhibition of 11 indicated the competitive manner towards maltase and sucrase. The potent inhibition of these compounds was elaborated by docking study, in which their binding profiles towards key amino acid residues in the active site were similar to that of voglibose. Therefore, introduction of propane-1,3-diol moiety to suitable cyclohexane core structure such as aminoquercitol would be a potential approach to discover a new series of effective α-glucosidase inhibitors.
authors.affiliation: Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Wisuttaya
authors.initials: W
authors.lastname: Worawalai
authors.affiliation: Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Pornthep
authors.initials: P
authors.lastname: Sompornpisut
authors.affiliation: Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Sumrit
authors.initials: S
authors.lastname: Wacharasindhu
authors.affiliation: Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand. Electronic address: preecha.p@chula.ac.th.
authors.forename: Preecha
authors.initials: P
authors.lastname: Phuwapraisirisan
mesh_terms: D000818:Animals; D001665:Binding Sites; D054812:Cyclitols / Q000737:chemistry*; D015870:Gene Expression; D065089:Glycoside Hydrolase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D007294:Inositol / Q000031:analogs & derivatives* / Q000737:chemistry; D007422:Intestines / Q000737:chemistry / Q000201:enzymology; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D051381:Rats; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013393:Sucrase / Q000037:antagonists & inhibitors / Q000737:chemistry; D000520:alpha-Glucosidases / Q000737:chemistry*
chemical_list: D054812:Cyclitols; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D008024:Ligands; C483225:proto-quercitol; D007294:Inositol; D000520:alpha-Glucosidases; D013393:Sucrase; C102817:voglibose
keywords: Cyclitol; Diabetes mellitus; Glucosidase; Quercitol; Serinol; Voglibose