title: Design, synthesis, and docking of highly hypolipidemic agents: Schizosaccharomyces pombe as a new model for evaluating alpha-asarone-based HMG-CoA reductase inhibitors.
abstract: 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.
authors.affiliation: 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.
authors.forename: Nancy
authors.initials: N
authors.lastname: Argüelles
authors.forename: Eugenia
authors.initials: E
authors.lastname: Sánchez-Sandoval
authors.forename: Aarón
authors.initials: A
authors.lastname: Mendieta
authors.forename: Lourdes
authors.initials: L
authors.lastname: Villa-Tanaca
authors.forename: Leticia
authors.initials: L
authors.lastname: Garduño-Siciliano
authors.forename: Fabiola
authors.initials: F
authors.lastname: Jiménez
authors.forename: María Del Carmen
authors.initials: Mdel C
authors.lastname: Cruz
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
authors.forename: Germán
authors.initials: G
authors.lastname: Chamorro-Cevallos
authors.forename: Joaquín
authors.initials: J
authors.lastname: Tamariz
mesh_terms: D000081248:Allylbenzene Derivatives; D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D003198:Computer Simulation; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012568:Schizosaccharomyces / Q000187:drug effects*
chemical_list: D000081248:Allylbenzene Derivatives; D000840:Anisoles; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C012195:asarone; D006903:Hydroxymethylglutaryl CoA Reductases