Novel 1,2,4-oxadiazole compounds as PPAR-alpha ligand agonists: a new strategy for the design of antitumour compounds

摘要

Modulation of PPAR-alpha by natural ligands is a novel strategy for the development of anticancer therapies. A series of 16 compounds based on the structure of 3-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,4-oxadiazole (natural compound) with antitumour potential were designed and synthesised. The cytotoxicity and PPAR agonist activity of these synthetic 1,2,4-oxadiazoles were evaluated in the A-498 and DU 145 tumour cell lines. Preliminary biological evaluation showed that most of these synthetic 1,2,4-oxadiazoles are less cytotoxic (sulforhodamine B assay) than the positive control WY-14643. Regarding the PPAR-alpha modulation, compound 16 was the most active, with EC50 = 0.23-0.83 mu M (PPAR-alpha). Additionally, compound 16 had a similar activity to the natural compound (EC50 = 0.18-0.77 mu M) and was less toxic in the RPTEC and WPMY-1 cell lines (non-tumour cells) (CC50 = 81.66-92.67 mu M) than the natural compound. Looking at the link between chemical structure and activity, our study demonstrates that changes to the natural 1,2,4oxadiazole at the level of the thiophenyl residue can lead to new agonists of PPAR-alpha with promising antitumour activity.