期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 48, 期 4, 页码 946-961出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm049389h
关键词
-
资金
- NCI NIH HHS [1R44CA99435, CA91632] Funding Source: Medline
- NIDDK NIH HHS [1R43DK65423] Funding Source: Medline
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 <38 mug/mL). Finally, a third subclass (16b, 29, 30) is also active against FAS (IC50 = less than or equal to20 mug/mL), is cytotoxic to cancer cells (IC50 <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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据