Establishment Of Telomerase Protein Model And Discovery Of Telomerase Inhibitors With Anticancer Activity

Cancer has become one of the major threats to people's health as its morbidity and mortality increase year by year.In China,the number of people suffering from cancer has increased year after year.Studies have shown that telomerase is closely related to the occurrence of cancer.As one of the important anti-cancer targets,many telomerase inhibitors have been reported to inhibit the proliferation of cancer cells.However,there are many problems in these inhibitors,such as low activity and poor stability.To this end,our group established a three-dimensional model of telomerase by using homologous modeling methods.Based on this receptor,eight telomerase inhibitors 5a-5h containing N-acyl-4,5-dihydropyrazole scaffold were designed and synthesized by using a structure-based design method of computer-aided drug design(CADD).The antiproliferative activities of these compounds were studied against three cancer cell lines,SGC-7901,Hep-G2 and MGC-803.Compound 5c showed anti-proliferative activity against all three types of cells,and its EC50 values for SGC-7901 and MGC-803 cells were 2.06 ± 0.17 and 2.89 ± 0.62 ?M,respectively,both superior to the positive control 5-fluorouracil..In order to explore whether this compound can produce anticancer activity through telomerase inhibition,its telomerase inhibition was evaluated with an IC50 value of 1.86 ± 0.51 ?M,which was superior to the positive control ethidium bromide.When the core is replaced by N-sulfonyl-4,5-dihydropyrazole,compounds 8a-8i are obtained.It is worth noting that the anti-cancer cell proliferation activities and telomerase inhibitory activities of 8a-8i were significantly lower than 5a-5h.Due to its good activity and low molecular weight,compound 5c can be used as a molecular fragment for molecular fragment-based research to lay a foundation for exploring more novel potent telomerase inhibitors.