Synthesis of Novel b-Lactone Inhibitors of Fatty Acid Synthase.

[摘要]：(Heterocyclic Compounds (One Hetero Atom)) Section Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncol. 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 b-lactone as the central pharmacophore, 28 novel congeners, e.g. I (R = H, CH2CHMe2, CH2Ph, etc.), were synthesized and examd. Structural features such as the length of the a- and b-alkyl chains, their chem. compn., and amino ester substitutions were altered and the resulting compds. explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochem. 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 soly. compared to orlistat. These findings support the idea that an orlistat congener can be optimized for use in a preclin. drug design and for clin. drug development.

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