Design and synthesis of new coumarin hybrids and insight into their mode of antiproliferative action.
Molecular hybridization approach was used to synthesize three series of coumarin based hybrids by conglomerate a substituted chalcones, acrylohydrazides, and pyridines moieties with 8-methoxy coumarin. The hybrids showed significant cytotoxic activity against liver cancer Hep G2 and Leukemia K562 cell lines with IC50 values 0.49-3.96μM, 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 0.65-2.02μM. Interestingly, the acrylohydrazide hybrid 4c showed the highest cytotoxic activity against the leukemia cell line (K562) with IC50 value of 0.49μM. 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 suggesting 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.
['Elshemy|Heba A H|HAH|', 'Zaki|Mohamed A|MA|']
D000970:Antineoplastic Agents D017209:Apoptosis D002453:Cell Cycle D045744:Cell Line, Tumor D049109:Cell Proliferation D003374:Coumarins D004305:Dose-Response Relationship, Drug D015195:Drug Design D004354:Drug Screening Assays, Antitumor D006801:Humans D015394:Molecular Structure D013329:Structure-Activity Relationship
Coumarins Antiproliferative Molecular hybridization Chalcones Acrylohydrazide Apoptosis Caspase Bcl-2 BAX