Synthesis and biological evaluation of novel triazoles linked 7-hydroxycoumarin as potent cytotoxic agents.

Cancer is regarded as second leading cause of death worldwide. Therefore, there is a high demand for the discovery, development and improvement of novel anti-cancer agents which could efficiently prevent proliferative pathways and clonal expansion of cells.

In view of this, a new series of bioactive scaffolds viz triazoles linked 7-hydroxycoumarin (1) were synthesized using click chemistry approach.

All the synthesized compounds were screened for cytotoxicity against a panel of seven different human cancer cell lines viz. Colon (Colo-205 and HCT-116), breast (MCF-7), lung (NCI-H322 and A549), prostate (PC-3) and skin (A-431) using 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) assay.

Among all tested analogs, compound 5, displayed better cytotoxic activity as compared to the parent 7- hydroxycoumarin (1) with IC50 of 5.1, 22.7, 14.3 and 10.2 μM against breast (MCF-7), lung (NCI- H322), prostate (PC-3) and skin (A-431) cancer cell lines, respectively; the compound 5 was 8-fold more sensitive against MCF-7 than the parent 7-hydroxycoumarin. Moreover, Compound 5 induced both cytotoxic as well as cytostatic effects via induction of apoptosis and G1 phase arrest, respectively in breast cancer cells (MCF-7). The apoptotic cell population enhanced to 18.8% at 8 μM of 5 from 9.8% in case of negative control, while G1 phase arrest increased to 54.4% at 8 μM compared to negative control of 48.1%. Moreover, Compound 5 also exhibited a remarkable decrease in mitochondrial membrane potential (ΛΨm) leading to apoptosis of cancer cells used.

The structure-activity relationship study revealed that the derivatives bearing electron-withdrawing substituents were more effective. The present study resulted in identification of the compounds demonstrating broad spectrum cytotoxic activity.