Novel 1,3,4-oxadiazole chalcogen analogues: Synthesis and cytotoxic activity.

ABSTRACT

A small library of novel 1,3,4-oxadiazole bioisosteres was synthesized and their cytotoxic activity evaluated in vitro. Five of the new derivatives (3, 6, 11, 14 and 15) showed high potency against different human cancer cell lines, with 14 being the most interesting compound endowed with IC50 ranging from 0.005 to 0.091 µM. Preliminary SAR studies have suggested that the-chlorine atom in ortho position of the phenyl ring on the 1,3,4-selenadiazole is important for antitumor potency in vitro. Notably, these new compounds showed stronger anti-tumor activity than the previously synthesized and published oxadiazole lead compound 2. Furthermore, the cytotoxic effect was only relevant in tumor cells compared to human primary cells. These results suggest that the nature of the selenadiazole and thiadiazole rings may be even more important for antitumor potency in vitro than the nature of the previously described oxadiazole. All five compounds resulted in a G2/M arrest of the cell cycle and activated an apoptotic response. The colony formation assay showed the long-term effect of the compounds on tumor lines in vitro. Immunofluorescence analysis of ß-tubulin indicated that all compounds interacted with micro-tubulin organization and mitotic spindle formation causing aberrant cell formation. For these reasons, the new molecules 3, 6, 11, 14 and 15 could be good candidates in preventive and chemotherapeutic strategies.