Design, synthesis, and docking of highly hypolipidemic agents: Schizosaccharomyces pombe as a new model for evaluating alpha-asarone-based HMG-CoA reductase inhibitors
Por:
Argüelles N., Sánchez-Sandoval E., Mendieta A., Villa-Tanaca L., Garduno-Siciliano, L, Jiménez F., Cruz, MD, Medina-Franco J.L., Chamorro-Cevallos G., Tamariz J.
Publicada:
15 jun 2010
Resumen:
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.
Filiaciones:
Argüelles N.:
Laboratorio de Toxicología Preclínica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala s/n, 11340 México, D.F., Mexico
Sánchez-Sandoval E.:
Laboratorio de Genética Microbiana, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala, 11340 México, D.F., Mexico
Mendieta A.:
Centro de Investigación en Biotecnología Aplicada, IPN, Carretera Estatal Sta. Ines Km 1.5, Tepetitla, 90700 Tlaxcala, Mexico
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala, 11340 México, D.F., Mexico
Villa-Tanaca L.:
Laboratorio de Genética Microbiana, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala, 11340 México, D.F., Mexico
Jiménez F.:
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala, 11340 México, D.F., Mexico
Medina-Franco J.L.:
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States
Chamorro-Cevallos G.:
Laboratorio de Toxicología Preclínica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala s/n, 11340 México, D.F., Mexico
Tamariz J.:
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala, 11340 México, D.F., Mexico
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