McFadden Jill M, Medghalchi Susan M, Thupari Jagan N, Pinn Michael L, Vadlamudi Aravinda, Miller Katherine I, Kuhajda Francis P, Townsend Craig A
Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218, USA.
J Med Chem. 2005 Feb 24;48(4):946-61. doi: 10.1021/jm049389h.
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) = <or=20 microg/mL), are nontoxic (MCF-7, 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) = <or=15 microg/mL), causes weight loss (>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) = <or=20 microg/mL), is cytotoxic to cancer cells (IC(50) < 25 mg/mL), and does not cause weight loss in BalbC mice. These studies identify thiolactomycin as a promising template for the development of new selective cancer and obesity treatments.
脂肪酸合酶（FAS）催化从乙酰引物与丙二酰辅酶A添加的两个碳单元的顺序缩合合成棕榈酸酯。抑制哺乳动物FAS的β-酮酰基合酶结构域会导致在体外和体内对各种癌细胞系产生选择性细胞毒性。此外，FAS抑制剂可导致小鼠食物摄入量和体重降低。天然存在的硫代乳霉素（TLM）被用作模板来开发一类新型的I型FAS抑制剂。通过灵活的合成方法，获得了具有选择性FAS活性并显示抗癌和减肥效果的TLM结构类似物家族。化合物13a和13d抑制纯FAS（ZR-75-1乳腺癌，IC50 =≤20μg/mL），无毒（MCF-7，IC50 => 50μg/mL），并在BalbC小鼠中显示出有效的体重减轻（> 5%）。TLM衍生物的另一个亚类（23b-d，31a）表现出FAS活性（IC50 =≤15μg/mL），导致体重减轻（> 5%），并且对癌细胞具有细胞毒性（IC50 < 38μg/mL）。最后，第三个亚类（16b，29，30）也对FAS有活性（IC50 =≤20μg/mL），对癌细胞具有细胞毒性（IC50 < 25mg/mL），并且在BalbC小鼠中不会导致体重减轻。这些研究表明硫代乳霉素是开发新型选择性癌症和肥胖症治疗方法的有前景的模板。
