title: Design and Synthesis of Labystegines, Hybrid Iminosugars from LAB and Calystegine, as Inhibitors of Intestinal α-Glucosidases: Binding Conformation and Interaction for ntSI.
abstract: This paper identifies the required configuration and orientation of α-glucosidase inhibitors, miglitol, α-1-C-butyl-DNJ, and α-1-C-butyl-LAB for binding to ntSI (isomaltase). Molecular dynamics (MD) calculations suggested that the flexibility around the keyhole of ntSI is lower than that of ctSI (sucrase). Furthermore, a molecular-docking study revealed that a specific binding orientation with a CH-π interaction (Trp370 and Phe648) is a requirement for achieving a strong affinity with ntSI. On the basis of these results, a new class of nortropane-type iminosugars, labystegines, hybrid iminosugars of LAB and calystegine, have been designed and synthesized efficiently from sugar-derived cyclic nitrones with intramolecular 1,3-dipolar cycloaddition or samarium iodide catalyzed reductive coupling reaction as the key step. Biological evaluation showed that our newly designed 3(S)-hydroxy labystegine (6a) inherited the selectivity against intestinal α-glucosidases from LAB, and its inhibition potency was 10 times better than that of miglitol. Labystegine, therefore, represents a promising new class of nortropane-type iminosugar for improving postprandial hyperglycemia.
authors.affiliation: †Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.affiliation: ‡Beijing National Laboratory of Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Zhao-Lan
authors.initials: ZL
authors.lastname: Zhang
authors.affiliation: ‡Beijing National Laboratory of Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Hong-Yao
authors.initials: HY
authors.lastname: Wang
authors.affiliation: ‡Beijing National Laboratory of Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Yue-Mei
authors.initials: YM
authors.lastname: Jia
authors.affiliation: ‡Beijing National Laboratory of Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Chu-Yi
authors.initials: CY
authors.lastname: Yu
authors.affiliation: †Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kinami
authors.affiliation: †Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hirokami
authors.affiliation: †Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Tsuji
authors.affiliation: †Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
authors.affiliation: §Institute of Biological, Environmental and Rural Sciences, Phytoquest Limited, Plas Gogerddan, Aberystwyth, Ceredigion SY23 3EB, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nash
authors.affiliation: ⊥Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.|∥National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, PR China.
authors.forename: George W J
authors.initials: GW
authors.lastname: Fleet
authors.affiliation: #School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Koseki
authors.affiliation: #School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Nakagome
authors.affiliation: #School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
mesh_terms: D001089:Arabinose / Q000737:chemistry; D001665:Binding Sites / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D050113:Imino Furanoses / Q000737:chemistry; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007422:Intestines / Q000201:enzymology; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009662:Nortropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013393:Sucrase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013402:Sugar Alcohols / Q000737:chemistry; D014326:Tropanes / Q000737:chemistry; D000520:alpha-Glucosidases / Q000378:metabolism*
chemical_list: C000599413:3-hydroxylabystegine; D004791:Enzyme Inhibitors; D050113:Imino Furanoses; D050111:Imino Sugars; D009662:Nortropanes; D013402:Sugar Alcohols; D014326:Tropanes; C055033:calystegin; C058137:1,4-dideoxy-1,4-iminoarabinitol; D001089:Arabinose; D000520:alpha-Glucosidases; D013393:Sucrase