title: Synthesis of novel beta-lactone inhibitors of fatty acid synthase.
abstract: Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a beta-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the alpha- and beta-alkyl chains, their chemical composition, and amino ester substitutions were altered and the resulting compounds explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochemical assays relative to orlistat. Three of that subset, including the natural product valilactone, also display an increased potency in inducing tumor cell death and improved solubility compared to orlistat. These findings support the idea that an orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development.
authors: NCI Cancer Center, The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors: Robyn D
authors: RD
authors: Richardson
authors: Gil
authors: G
authors: Ma
authors: Yatsandra
authors: Y
authors: Oyola
authors: Manuel
authors: M
authors: Zancanella
authors: Lynn M
authors: LM
authors: Knowles
authors: Piotr
authors: P
authors: Cieplak
authors: Daniel
authors: D
authors: Romo
authors: Jeffrey W
authors: JW
authors: Smith
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005347:Fibroblasts; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D000077403:Orlistat; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; C054478:valilactone; D000077403:Orlistat; D064429:Fatty Acid Synthases