Synthesis And Biological Evaluation Of Novel 7-hydroxy-4-phenylchromen-2-one-linked To Triazole Moieties As Potent Antitumor Agents

Cancer is one of the diseases with high morbidity and mortality.In China,the number of cancer patients and cancer deaths is increasing every year.At present,the treatment of cancer is mainly drug treatment(chemotherapy)and surgery,however,chemotherapy drugs can not only kill cancer cells in the body but also can kill normal cells,And the toxic side effects caused by drugs bring great pain to the patient's body,and even some patients have developed resistance to anticancer drugs.Surgical treatment is not available for many cancers.In recent years,some small molecule anti-cancer drugs have been discovered and developed.However,There is still a need to develop new antitumor drugs that are selective and safe for tumors.According to the literature,7-hydroxy-4-phenylcoumarin and its derivatives have a wide range of pharmacological activities.Some derivatives of 7-hydroxy-4-phenylcoumarin exhibit anti-inflammatory,antibacterial,anticancer,anti-oxidant and other biological activities,and new therapeutic drugs are screened out.In this paper,7-hydroxy-4-phenylcoumarin was synthesized from ethyl benzoylacetate.A new series of novel 7-hydroxy-4-phenylchromen-2-one(la)-linked 1,2,4-triazoles or 1,2,3-triazoles were synthesised using a click chemistry approach.All derivatives were subjected to 3-(4,5-dimethylthiazol-yl)-diphenyl tetrazolium bromide(MTT)cytotoxicity screening against a panel of six different human cancer cell lines(AGS,MGC-803,HCT-116,A-549,HepG2,and HeLa)to assess their cytotoxic potential.Among the tested molecules,some of the analogues showed better cytotoxic activity than that shown by the 7-hydroxy-4-phenylchro-men-2-one(la).Of the synthesised 1,2,4-triazoles,the 7-((4-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-4-phenyl-2H-chromen-2-one(4d)showed the best activity,with an IC50 of 2.63±0.17 ?M against AGS cells.However,among the 7-hydroxy-4-(4-methox-yphenyl)-2H-chromen-2-one derivatives of the 1,2,4-triazoles(5a-5e),the coumarin derivatives exhibited greatly reduced activity against cancer cell lines,with compound 5a exhibiting only moderate activity against the AGS cell line,with an IC50 value of 16.80±0.83 ?M.Among the 1,2,3-triazoles(7a-7e),compound 7c was the most active,with an IC50 of 48.16±0.46 ?M and selective activity against the MGC-803 cancer cell line.Further flow cytometry assays demonstrated that compound 4d exerts its antiproliferative effects by arresting cells in the G2/M phase of the cell cycle and by inducing apoptosis.Collectively,our results indicate that In the series of 1,2,4-triazole derivatives(4a-4m,5a-5e),The antitumor activity of 4-phenyl derivatives(5a-5e)substituted by the methoxy group was significantly reduced.the 1,2,4-triazole derivatives have a significantly stronger antitumour activity than 1,2,3-triazole derivatives.Most of the compounds exhibited better antitumour activity than the positive control drug 5-fluorouracil.