Application of a flexible synthesis of (5R)-thiolactomycin to develop new inhibitors of type I fatty acid synthase.

McFadden, Jill M; Medghalchi, Susan M; Thupari, Jagan N; Pinn, Michael L; Vadlamudi, Aravinda; Miller, Katherine I; Kuhajda, Francis P; Townsend, Craig A

McFadden, Jill M; Medghalchi, Susan M; Thupari, Jagan N; Pinn, Michael L; Vadlamudi, Aravinda; Miller, Katherine I; Kuhajda, Francis P; Townsend, Craig A.

Afiliación

McFadden JM; Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218, USA.

J Med Chem ; 48(4): 946-61, 2005 Feb 24.

Article en En | MEDLINE | ID: mdl-15715465

RESUMEN

Fatty acid synthase (FAS) catalyzes the synthesis of palmitate from the sequential condensation of an acetyl primer with two carbon units added from malonyl-CoA. Inhibition of the beta-ketoacyl synthase domain of mammalian FAS leads to selective cytotoxicity to various cancer cell lines in vitro and in vivo. Also, inhibitors of FAS can cause reduced food intake and body weight in mice. Naturally occurring thiolactomycin (TLM) was used as a template to develop a new class of type I FAS inhibitors. Using a flexible synthesis, families of TLM structural analogues were obtained that possess selective FAS activity and display anticancer and weight loss effects. Compounds 13a and 13d inhibit pure FAS (ZR-75-1 breast cancer, IC(50) = 50 microg/mL), and display effective weight loss in BalbC mice (>5%). Another subclass of TLM derivatives (23b-d, 31a) exhibits FAS activity (IC(50) = 5%), and is cytotoxic to cancer cells (IC(50) < 38 microg/mL). Finally, a third subclass (16b, 29, 30) is also active against FAS (IC(50) =

Asunto(s)

Fármacos Antiobesidad/síntesis química; Antineoplásicos/síntesis química; Ácido Graso Sintasas/antagonistas & inhibidores; Tiofenos/síntesis química; Animales; Fármacos Antiobesidad/química; Fármacos Antiobesidad/farmacología; Antineoplásicos/química; Antineoplásicos/farmacología; Peso Corporal/efectos de los fármacos; Línea Celular Tumoral; Ensayos de Selección de Medicamentos Antitumorales; Ácido Graso Sintasas/química; Humanos; Ratones; Ratones Endogámicos BALB C; Modelos Moleculares; Estereoisomerismo; Relación Estructura-Actividad; Tiofenos/química; Tiofenos/farmacología

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiofenos / Fármacos Antiobesidad / Ácido Graso Sintasas / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2005 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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