Design and synthesis of new coumarin hybrids and insight into their mode of antiproliferative action

Research Abstract

Molecular hybridization approach was used to synthesize three series of coumarin based hybrids by conglomerate a substituted chalcones, acrylohydrazides, and pyridines moiety with 8-methoxy coumarin. The hybrids showed significant cytotoxic activity against liver cancer Hep G2 and Leukemia K562 cell lines with IC50 value 0.49-3.96 μM, comparable to the positive controls and exhibited weak activity against the normal cell line WI-38, thus indicating selectivity toward the tumor cells. Coumarin-chalcone hybrids 2a-c have demonstrated the most promising activity against both cancer cell lines with IC50 values of 0.65-2.02 μM. Interestingly, the acrylohydrazide hybrid 4c showed the highest cytotoxic activity against the leukemia cell line (K562) with IC50 value of 0.49 µM. All the investigated coumarin hybrids were able to increase the caspase-3 and caspase-9 proteins level expression relative to that of the untreated cells suggest that coumarin hybrids-induced apoptosis was, in part, due to activation of caspases 3 and 9. Apoptosis was further confirmed with down-regulation of Bcl-2 and up-regulation of Bax protein expression level. Furthermore, cell cycle analysis of 2a and 4c showed apoptotic signals activation, as a consequence of arrest in G2/M phase. Results of our study can shed light on coumarin-based hybrids as promising anticancer leads.

Research Keywords

coumarin - chalcone