Synthesis of Novel β-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 β-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the α- and β-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.

Assay and inhibition of diacylglycerol lipase activity

“…Several analogs (THL 3 , OMDM-188 4 , and the new L - allo analog 5 ) showed good selectivity for diacylglycerol lipase over monoacylglycerol lipase and fatty acid amide hydrolase enzymes. Future studies can include shorter alkyl chain analogs similar to the fatty acid synthase inhibitors from the Romo group 42 that might have better solubility and membrane penetration properties.…”

The Potential of 11C-acetate PET for Monitoring the Fatty Acid Synthesis Pathway in Tumors

“…Since the discovery of orlistat as a FASN inhibitor, a number of orlistat analogs have been developed that also target the FASN-TE domain. These newly synthesized analogs share with orlistat a beta-lactone moiety as the distinguishing chemotype [70]. Beta-lactam derivatives of orlistat have also been described [71].…”

(+)- and (−)-ganodilactone, a pair of meroterpenoid dimers with pancreatic lipase inhibitory activities from the macromycete Ganoderma leucocontextum

“…Owing to the high prevalence and incidence of complicating diseases such as cardiovascular disease, diabetes, osteoarthritis and cancer, combating obesity is one of the top priorities for World Health Organization (WHO). [3][4][5] Discovery of potential anti-obese natural product leads have long been one of our key research aspects in the field of secondary metabolites from mushroom and we have achieved key progresses both in discovery natural pancreatic lipase inhibitors and structure optimisation of potential antiobese leads. 2 The urgent requirements for cost-effective anti-obese medications to extend the lifespan have aroused great attentions for medicinal chemists.…”