Novel anticancer thiazolidine molecules: Design, synthesis and evaluation

Cancer results from unregulated cell growth. Reactivating cell death in cancer cells, i.e. apoptosis, is a classical anticancer therapeutic strategy. The apoptosis-inducer property of the (2RS,4R)-2-phenyl-3-propinoyl-thiazolidine-4-carboxylic acid ethyl ester (ALC67) molecule has been discovered recently. To elucidate the mechanism of action of this molecule and to evaluate the impact of the phenyl group that the thiazolidine ring presents at its second position on the cytotoxicity, we developed eleven ALC 67 analogues (3a-3m) replacing the phenyl moiety with various aliphatic and aromatic groups. The synthesis of ALC67 analogues required three major steps. The first step consisted of the formation of the thiazolidine ring using L-cysteine and an aldehyde (1a-1m). Then, the thiazolidine ring was modified in order to first introduce the ethyl ester moiety (2a-2m) and then the propionyl group (3a-3m). A total of thirty three novel molecules were obtained and most of compounds were characterized by FT-IR, 1H NMR, 13C NMR and LC-MS. The cytotoxic activity of the novel (2RS,4R)-2-phenyl-3-propinoyl-thiazolidine-4-carboxylic acid ethyl ester derivatives (3a-3m) were evaluated on human liver HUH7 and Mahlavu hepatocellular carcinoma cell (HCC) lines with the sulforhodamine B (SRB) assay. Results demonstrated that the antiproliferative property was conserved when the phenyl moiety was replaced. Thus, with this investigation a novel class of thiazolidine derivatives with promising anticancer activity was developed. Keywords: Thiazolidine, terminal alkyne, anticancer, apoptosis.