title: Design and synthesis of new coumarin hybrids and insight into their mode of antiproliferative action.
abstract: 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 IC50values 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 IC50values of 0.65-2.02μM. Interestingly, the acrylohydrazide hybrid 4c showed the highest cytotoxic activity against the leukemia cell line (K562) with IC50value 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.
authors.affiliation: Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address: ha_elshemy@yahoo.com.
authors.forename: Heba A H
authors.initials: HAH
authors.lastname: Elshemy
authors.affiliation: Department of Pharmacognosy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, United States.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Zaki
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; C030123:coumarin
keywords: Acrylohydrazide; Antiproliferative; Apoptosis; BAX; Bcl-2; Caspase; Chalcones; Coumarins; Molecular hybridization