Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 18, Issue 12, Pages 4238-4248Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.04.096
Keywords
Alpha-asarone; Docking; HMG-CoA reductase; Hypocholesterolemic activity; Schizosaccharomyces pombe
Funding
- CONACyT [G-34851-M, Salud-69984]
- DGAPA [NI 202101]
- PIFI-IPN
- EDI/IPN
- COFAA/IPN programs
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A series of alpha-asarone-based analogues was designed by conducting docking experiments with published crystal structures of human HMG-CoA reductase. Indeed, synthesis and evaluation of this series showed a highly hypocholesterolemic in vivo activity in a murine model, as predicted by previous docking studies. In agreement with this model, the polar groups attached to the benzene ring could play a key role in the enzyme binding and probably also in its biological activity, mimicking the HMG-moiety of the natural substrate. The hypolipidemic action mechanism of these compounds was investigated by developing a simple, efficient, and novel model for determining HMG-CoA reductase inhibition. The partial purification of the enzyme from Schizosaccharomyces pombe allowed for testing of alpha-asarone- and fibrate-based analogues, resulting in positive and significant inhibitory activity. (C) 2010 Elsevier Ltd. All rights reserved.
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