SYNTHESIS OF ALFA-ALKYLIDEN-GAMMA-LACTONES AS FAS INHIBITORS

a-Methylenelactones have received much attention due to the biological activity exhibited by natural products containing this structural moiety [1]. Cytotoxic, anti-inflammatory, phytotoxic, allergenic and antimicrobial properties are shown not only by highly functionalized, complex sesquiterpene lactones but also simple representatives were studied for their biological effects. Besides, compared to normal human tissues, many common human cancers, express high levels of fatty acid synthase (FAS), the primary enzyme responsible for the synthesis of fatty acids. This differential expression of FAS between normal tissues and cancer has led to the notion that FAS is a target for anticancer drug development [2]. A new series of a-methylene-g.butyrolactones has been synthesized with an alkylidene moiety in 3 position and a substution in 5 position. All the compounds were tested against PANC-1, HCT-116, Lovo, MCF-7 and MDA-231-MB tumor cell lines by MTT assay to different concentrations of the above compounds (4.1x10-7-3.0x10-4 ) after a 48 h exposition. The compound with R=H and R'= 3',5'- dimethoxyphenyl exhibited a pharmacological interesting cell toxicity profile in all cell lines with EC50 values similar to the reference compound cerulenine. References 1) F. Cateni et al. , European Journal of Medicinal Chemistry 41, (2006), 192-200. 2) F.P. Kuhajda et al. , Proc. Natl. Acad. Sci. USA 7, (2000), 3450-4.