Ma Zaki

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.

Monoamine oxidases inhibitors from Colvillea racemosa: Isolation, biological evaluation, and computational study

Bioassay-guided fractionation and chemical investigation of Colvillea racemosa stems led to identification of two new α, β-dihydroxydihydrochalcones, colveol A (1) and colveol B (2) along with fifteen known compounds. The structures were elucidated via interpretation of spectroscopic data. The absolute configurations of the dihydrochalcones 1 and 2 were assigned by a combination of chemical modification and electronic circular dichroism data. The isolated compounds were evaluated for their inhibition activity toward recombinant human monoamine oxidases (rhMAO-A and -B). Compound 1 demonstrated preferential inhibition against hMAO-A isoenzyme (IC50 0.62μM, SIA/B 0.02) while S-naringenin (13) and isoliquiritigein (15) demonstrated preferential hMAO-B inhibition (IC50 0.27 and 0.51μM, SIA/B 31.77 and 44.69, respectively). Fisetin (11) showed inhibition against hMAO-A with IC50 value of 4.62μM and no inhibitory activity toward hMAO-B up to 100μM. Molecular docking studies for the most active compounds were conducted to demonstrate the putative binding modes. It suggested that 1 interacts with Gln215, Ala111, Phe352, and Phe208 amino acid residues which have a role in the orientation and stabilization of the inhibitor binding to hMAO-A, while S-naringenin (13) occupies both entrance and substrate cavities and interacts with Tyr326, a critical residue in inhibitor recognition in hMAO-B.