title: Synthesis and highly potent hypolipidemic activity of alpha-asarone- and fibrate-based 2-acyl and 2-alkyl phenols as HMG-CoA reductase inhibitors.
abstract: In the search for new potential hypolipidemic agents, the present study focused on the synthesis of 2-acyl phenols (6a-c and 7a-c) and their saturated side-chain alkyl phenols (4a-c and 5a-c), and on the evaluation of their hypolipidemic activity using a murine Tyloxapol-induced hyperlipidemic protocol. The whole series of compounds 4-7 greatly and significantly reduced elevated serum levels of total cholesterol, LDL-cholesterol, and triglycerides, with series 6 and 7 showing the greatest potency ever found in our laboratory. At the minimum dose (25mg/kg/day), the latter compounds lowered cholesterol by 68-81%, LDL by 72-86%, and triglycerides by 59-80%. This represents a comparable performance than that shown by simvastatin. Experimental evidence and docking studies suggest that the activity of these derivatives is associated with the inhibition of HMG-CoA reductase.
authors.affiliation: Depto. de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico.
authors.forename: Aarón
authors.initials: A
authors.lastname: Mendieta
authors.affiliation: Centro de Investigación en Biotecnología Aplicada, IPN, Carretera Estatal Santa Inés Tecuexcomac-Tepetitla, Km 1.5, Tepetitla de Lardízabal, 90700 Tlaxcala, Mexico.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Jiménez
authors.affiliation: Laboratorio de Toxicología Preclínica, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico.
authors.forename: Leticia
authors.initials: L
authors.lastname: Garduño-Siciliano
authors.affiliation: Laboratorio de Toxicología Preclínica, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico.
authors.forename: Angélica
authors.initials: A
authors.lastname: Mojica-Villegas
authors.affiliation: Laboratorio de Genética Microbiana, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico.
authors.forename: Blanca
authors.initials: B
authors.lastname: Rosales-Acosta
authors.affiliation: Laboratorio de Genética Microbiana, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Villa-Tanaca
authors.affiliation: Laboratorio de Toxicología Preclínica, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico.
authors.forename: Germán
authors.initials: G
authors.lastname: Chamorro-Cevallos
authors.affiliation: Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, 04510 México, D.F., Mexico.
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
authors.affiliation: Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Meurice
authors.affiliation: Depto. de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico.
authors.forename: Rsuini U
authors.initials: RU
authors.lastname: Gutiérrez
authors.affiliation: Depto. de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico.
authors.forename: Luisa E
authors.initials: LE
authors.lastname: Montiel
authors.affiliation: Centro de Investigación en Biotecnología Aplicada, IPN, Carretera Estatal Santa Inés Tecuexcomac-Tepetitla, Km 1.5, Tepetitla de Lardízabal, 90700 Tlaxcala, Mexico. Electronic address: carmencruz25@yahoo.com.mx.
authors.forename: María Del Carmen
authors.initials: Mdel C
authors.lastname: Cruz
authors.affiliation: Depto. de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico. Electronic address: jtamarizm@gmail.com.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Tamariz
mesh_terms: D000081248:Allylbenzene Derivatives; D000818:Animals; D000840:Anisoles / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D020134:Catalytic Domain; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000081248:Allylbenzene Derivatives; D000840:Anisoles; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010636:Phenols; D014280:Triglycerides; C012195:asarone; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: 2-Acyl phenols; 2-Alkyl phenols; Docking; HMG-CoA reductase; Hypolipidemic; Phenoxyacetic