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Title: a-Glucosidase inhibitors from a Xylaria feejeensis associated with Hintonia latiflora

item RIVERA-CHAVCEZ, JOSE - Universidad Nacional Autonoma De Mexico
item FIGUEROA, MARIO - Universidad Nacional Autonoma De Mexico
item GONZALEZ, MARIA DEL CARM - Universidad Nacional Autonoma De Mexico
item Glenn, Anthony - Tony
item MATA, RACHEL - Universidad Nacional Autonoma De Mexico

Submitted to: Natural Products Report
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/21/2015
Publication Date: 2/23/2015
Citation: Rivera-Chavcez, J., Figueroa, M., Gonzalez, M., Glenn, A.E., Mata, R. 2015. a-Glucosidase inhibitors from a Xylaria feejeensis associated with Hintonia latiflora. Natural Products Report. 978(40:730-735

Interpretive Summary: Many fungi infect plants as “endophytes” that grow between plant cells and often cause little or no harmful effects to the plants. Many of these fungi produce a broad array of metabolites. The plant Hintonia latiflora is noted in Mexico for its anti-diabetic medicinal properties, and there is increasing interest whether endophytic fungi and their metabolites may be responsible for the positive medicinal properties. The ascomycete fungus Xylaria feejeensis was isolated as an endophyte of this plant. Various metabolites produced by this fungus in culture were extracted and identified, including two compounds not previously known. Studies were performed to evaluate the effectiveness of these compounds as inhibitors of the enzyme a-glucosidase. Cells use this enzyme to break apart complex carbohydrates to generate glucose, which is then absorbed by the cells. Inhibition of this enzyme is an important strategy for the treatment of diabetes, since slower absorption of glucose prevents spikes in blood sugar. Thus, there is much interest in identifying new, effective inhibitory compounds as possible new drugs for the treatment of diabetes. The data showed two 4-hydroxymellein compounds had high potential as inhibitors of a-glucosidase similar to acarbose, the compound currently used to treat diabetic individuals.

Technical Abstract: Two new compounds, pestalotin 4'-O-methyl-ß-mannopyranoside (1) and 3S,4R-(+)-4-hydroxymellein (2), were isolated from an organic extract of a Xylaria feejeensis, which was isolated as an endophytic fungus from Hintonia latiflora. In addition, the known compounds 3S,4S-(+)-4-hydroxymellein (3), 3S-(+)-8-methoxymellein (4), and the quinone derivatives 2-hydroxy-5-methoxy-3-methylcyclohexa-2,5-diene-1,4-dione (5), 4S,5S,6S-4-hydroxy-3-methoxy-5-methyl-5,6-epoxycyclohex-2-en-1-one (6), and 4R,5R-dihydroxy-3-methoxy-5-methylcyclohexen-2-en-1-one (7) were obtained. The structures of 1 and 2 were elucidated using a set of spectroscopic and spectrometric techniques. The absolute configuration of the stereogenic centers of 1 and 2 was determined using ECD spectroscopy combined with time-dependent density functional theory calculations. In the case of 1, comparison of the experimental and theoretical 3J6-7 coupling constants provided further evidence for the stereochemical assignments. Compounds 2 and 3 inhibited Saccharomyces cerevisiae a-glucosidase (aGHY), with IC50 values of 441 ± 23 and 549 ± 2.5 µM, respectively. Their activity was comparable to that of acarbose (IC50 = 545 ± 19 µM), used as positive control. Molecular docking predicted that both compounds bind to aGHY in a site different from the catalytic domain, which could imply an allosteric type of inhibition.