Synthesis of novel C5-curcuminoid-fatty acid conjugates and mechanistic investigation of their anticancer activity

The first synthesis of C5-curcumin-fatty acid (C5-Curc-FA) conjugates was successfully performed. Through a two-step synthetic route, 10 analogs were synthesized for a structure-activity relationship (SAR) study. It was found that C5-Curc-FA conjugates containing either decanoic acid or palmitic acid moieties were cytotoxic against colorectal adenocarcinoma cell (CCL-229) at IC(50)s ranging from 22.5 to 56.1 mu g/mL, being 5c the most active C5-Curc-FA conjugate. Our results strongly suggests that a decanoic acid moiety at the meta position in C5-Curc-FA conjugates is important for their anticancer activity effect. Possible mechanisms for the anticancer activity of C5-Curc-FA conjugates were also investigated including apoptosis induction, mitochondrial damage and caspases activation. It was shown that 5c inhibited the luminescence activity of NF kappa B, a key signaling molecule involved in cell apoptosis and cell proliferation, at IC50 = 18.2 mu g/mL. In addition, it was demonstrated that 5c displayed significant apoptotic effect at GI(50) = 46.0 mu g/mL in colorectal adenocarcinoma cell line (ATCC CCL-222), which can be explained by the significant mitochondrial membrane permeabilization and caspases 3 and 7 activation effect of 5c. Finally, it was investigated that C-5-Curc-FA conjugates can affect the replication process of cancer cells, since compounds 5c, 5e, and 6c inhibited the relaxing activity of the human DNA topoisomerase I at minimum inhibitory concentrations (MICs) that range from 50 to 250 mu w/mL. Our results strongly support the hypothesis that the inhibition of both NFjB and DNA topoisomerase I by C5-Curc-FA conjugates is associated with their anticancer activity. (C) 2015 Elsevier Ltd. All rights reserved.