Application of a flexible synthesis of (5R)-thiolactomycin to develop new inhibitors of type I fatty acid synthase
Application of a flexible synthesis of (5R)-thiolactomycin to develop new inhibitors of type I fatty acid synthase
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DOI：
10.1021/jm049389h
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发表时间：
2005-02-24
影响因子：
7.3
通讯作者：
Townsend, CA
中科院分区：
文献类型：
--
作者：
McFadden, JM;Medghalchi, SM;Townsend, CA
脂肪酸合酶（FAS）催化棕榈酸酯的合成，所述棕榈酸酯由乙酰基引物与从丙二酰-CoA添加的两个碳单元的顺序缩合来合成。哺乳动物FAS的β-酮脂酰合酶结构域的抑制导致体外和体内对各种癌细胞系的选择性细胞毒性。此外，FAS的抑制剂可导致小鼠的食物摄入量和体重减少。天然存在的硫乳霉素（TLM）被用作开发一类新的I型FAS抑制剂的模板。使用灵活的合成，获得具有选择性FAS活性并显示抗癌和减肥作用的TLM结构类似物家族。化合物13 a和13 d抑制纯FAS（ZR-75-1乳腺癌，IC 50 =小于或等于20 μ g/mL），是无毒的（MCF-7，IC 50 = >50 μ g/mL），并且在BalbC小鼠中显示有效的体重减轻（>5%）。TLM衍生物的另一个亚类（23 b-d、31 a）表现出FAS活性（IC 50 =小于或等于15 μ g/mL），导致体重减轻（>5%），并且对癌细胞具有细胞毒性（IC 50
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, IC50 = less than or equal to20 mug/mL), are nontoxic (MCF-7, IC50 = >50 mug/mL), and display effective weight loss in BalbC mice (>5%). Another subclass of TLM derivatives (23b-d, 31a) exhibits FAS activity (IC50 = less than or equal to15 mug/mL), causes weight loss (>5%), and is cytotoxic to cancer cells (IC50