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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Obesity Agents / chemical synthesis*
  • Anti-Obesity Agents / chemistry
  • Anti-Obesity Agents / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Body Weight / drug effects
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Fatty Acid Synthases / antagonists & inhibitors*
  • Fatty Acid Synthases / chemistry
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology


  • Anti-Obesity Agents
  • Antineoplastic Agents
  • Thiophenes
  • thiolactomycin
  • Fatty Acid Synthases