title: 3-Hydroxypyrrolidine and (3,4)-dihydroxypyrrolidine derivatives: inhibition of rat intestinal α-glucosidase.
abstract: Thirteen pyrrolidine-based iminosugar derivatives have been synthesized and evaluated for inhibition of α-glucosidase from rat intestine. The compounds studied were the non-hydroxy, mono-hydroxy and dihydroxypyrrolidines. All the compounds were N-benzylated apart from one. Four of the compounds had a carbonyl group in the 2,5-position of the pyrrolidine ring. The most promising iminosugar was the trans-3,4-dihydroxypyrrolidine 5 giving an IC50 of 2.97±0.046 and a KI of 1.18 mM. Kinetic studies showed that the inhibition was of the mixed type, but predominantly competitive for all the compounds tested. Toxicological assay results showed that the compounds have low toxicity. Docking studies showed that all the compounds occupy the same region as the DNJ inhibitor on the enzyme binding site with the most active compounds establishing similar interactions with key residues. Our studies suggest that a rotation of ∼90° of some compounds inside the binding pocket is responsible for the complete loss of inhibitory activity. Despite the fact that activity was found only in the mM range, these compounds have served as simple molecular tools for probing the structural features of the enzyme, so that inhibition can be improved in further studies.
authors.affiliation: Centro de Química de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal.
authors.forename: Elisabete P
authors.initials: EP
authors.lastname: Carreiro
authors.affiliation: Departamento de Química, Universidade de Evora, Rua Romão Ramalho, 59, 7000 Evora, Portugal; Instituto de Ciências Agrárias e Ambientais Mediterrânicas (ICCAM), Apartado 94, 7002-554, Universidade de Évora, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Louro
authors.affiliation: Departamento de Química, Universidade de Evora, Rua Romão Ramalho, 59, 7000 Evora, Portugal; Centro de Química de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal.
authors.forename: Gizé
authors.initials: G
authors.lastname: Adriano
authors.affiliation: Instituto de Ciências Agrárias e Ambientais Mediterrânicas (ICCAM), Apartado 94, 7002-554, Universidade de Évora, Portugal.
authors.forename: Romina A
authors.initials: RA
authors.lastname: Guedes
authors.affiliation: Instituto de Ciências Agrárias e Ambientais Mediterrânicas (ICCAM), Apartado 94, 7002-554, Universidade de Évora, Portugal.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Vannuchi
authors.affiliation: Departamento de Química, Universidade de Evora, Rua Romão Ramalho, 59, 7000 Evora, Portugal; Instituto de Ciências Agrárias e Ambientais Mediterrânicas (ICCAM), Apartado 94, 7002-554, Universidade de Évora, Portugal.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Costa
authors.affiliation: Departamento de Química, Universidade de Evora, Rua Romão Ramalho, 59, 7000 Evora, Portugal; Instituto de Ciências Agrárias e Ambientais Mediterrânicas (ICCAM), Apartado 94, 7002-554, Universidade de Évora, Portugal; Center For Neurosciences and Cell Biology, University of Coimbra, Portugal.
authors.forename: Célia M M
authors.initials: CM
authors.lastname: Antunes
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.affiliation: Departamento de Química, Universidade de Evora, Rua Romão Ramalho, 59, 7000 Evora, Portugal. Electronic address: ajb@uevora.pt.
authors.forename: A J
authors.initials: AJ
authors.lastname: Burke
mesh_terms: D000818:Animals; D001156:Artemia / Q000187:drug effects / Q000254:growth & development; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D065089:Glycoside Hydrolase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007422:Intestines / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D000520:alpha-Glucosidases / Q000378:metabolism*
chemical_list: C540241:3,4-dihydroxypyrrolidine; D065089:Glycoside Hydrolase Inhibitors; D011759:Pyrrolidines; D000520:alpha-Glucosidases
keywords: 1-Benzyl-3,4-dihydroxypyrrolidine; 1-Benzyl-3-hydroxypyrrolidine; Rat intestinal cells; Small molecule inhibitor; α-Glucosidase