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Title: 3-Hydroxypyrrolidine and (3,4)-dihydroxypyrrolidine derivatives: inhibition of rat intestinal α-glucosidase
Authors: Carreiro, Elisabete P. 
Louro, Patrícia 
Adriano, Gizé 
Guedes, Romina A. 
Vannuchi, Nicholas 
Costa, Ana R. 
Antunes, Célia M. M. 
Guedes, Rita C. 
Burke, A. J. 
Keywords: 1-Benzyl-3-hydroxypyrrolidine; 1-Benzyl-3,4-dihydroxypyrrolidine; Small molecule inhibitor; α-Glucosidase; Rat intestinal cells
Issue Date: Jun-2014
Publisher: Elsevier
Citation: CARREIRO, Elisabete P. [et. al] - 3-Hydroxypyrrolidine and (3,4)-dihydroxypyrrolidine derivatives: inhibition of rat intestinal α-glucosidase. "Bioorganic Chemistry". ISSN 0045-2068. Vol. 54 (2014) p. 81–88
Serial title, monograph or event: Bioorganic Chemistry
Volume: 54
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.
ISSN: 0045-2068
DOI: 10.1016/j.bioorg.2014.04.007
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais

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