Design, Synthesis And Anticancer Activities Of Novel Coumarin-4,5-dihydropyrazole Targeting Telomerase

Based on computer aided drug design,44novel coumarin-dihydropyrazolo-chromoneskeleton derivatives as potential telomerase inhibitors have beensynthesized through Knoevenagel and Claisen-Schmidt condensation reactions,cyclization, acylation, substitution reaction of salicylaldehyde with ehhyl acetoacetate.Structures of the synthesized14compounds were confirmed by1H-NMR、13C-NMR、X-ray crystallography. Their anti-proliferative activity was evaluated by MTT methodwith Gastric cancer cell lines(MGC-803, SGC-7901), Breast cancer cell lines(Bcap-37), Hepatoma cells line (HEPG-2). The results showed that the14compoundstested have potent activity against the mentioned tumor cell lines and some of themwere even better than that of the commercial5-fluorouracil. Among them, compound8b-1showed the most potent anti-proliferative. Some title compounds were testedagainst telomerase by a modified TRAP assay, compound8b-1showed the mostpotent inhibitory activity with IC50=0.92±0.09μM. Docking simulation wasperformed to position compound8b-1into the telomerase (TERT) active site todetermine the probable binding model.