Design, Synthesis And Antitumor Activity In Vitro Evaluation Of Novel 1,2,4-triazine Derivatives

1,2,4-Triazine is one of the six membered ring bearing three nitrogens,1,2,4-triazine ring have a great variety of pharmacological effects,especially active as anti-tumor agents,anti-HIV agents,CRF receptor antagonists,antimicrobial and so on.In recent years,the study on anti-tumor activity of 1,2,4-Triazine compounds have become increasingly active and rapid development,such as the development of anti-tumor targeted drugs Tirapazamine and Brivanib.Based on the above research,we synthesized three series of 1,2,4-triazine derivatives.And then we evaluated its anti-tumor activity in vitro and analyzed its structure-activity relationship.The main research work is as follows:1.First,we reviewed the synthetic methods of 1,2,4-triazine and the antitumor activity of 1,2,4-triazine derivatives.2.By using condensation reaction,nucleophilic substitution and click chemistry and other organic reactions,twenty-two 5,6-diphenyl 1,2,4-triazine derivatives?seventeen 1,2,4-triazine-1,2,3-triazole derivatives and eight 3,5,6-trisubstrituted1,2,4-triazine derivatives.All the synthesized compounds were confirmed by¹HNMR?¹³CNMR and MS,Among them,35 compounds were not reported in the literature.Some of the synthetic routes have been optimized.3.We selected MTT assay to evaluate the vitro anti-tumor activity of the synthesized compounds.The results show that some of the compounds showed good in vitro antitumor activity against one or more tumor cell lines.Among the different substituted 1,2,4-triazine skeleton series compounds,most of the compounds had poor inhibitory activity against these three tumor cell lines,and the IC₅₀0 value of compound MO-10 against MGC-803 cells was 49.056±5.453?M,and the IC₅₀0 value of compound MO-23 against EC-109 cells was 1.643±0.142?M.In the1,2,4-triazine-1,2,3-triazole compound series,the compound MC-2 was tested against three types of tumors:MGC-803 cells,EC-109 cells and PC-3 cells.The inhibitory activity of the cells was better than the positive control drug 5-fluorouracil.Among the 3,5,6-trisubstituted-1,2,4-triazine series compounds,compound MH-4 exhibited a good inhibitory effect on MGC-803 cells with an IC₅₀0 value of 4.955±0.426?M.In summary,we synthesized twenty-two 1,2,4-triazine skeletons?seventeen1,2,4-triazine-1,2,3-triazolederivatives,andeightnew3,5,6-trisubstrituted1,2,4-triazine derivatives.And then we evaluate the vitro anti-tumor activity of the synthesized compounds.A total of 35 compounds have not been reported in the literature.The compounds with the best anti-tumor activity in vitro were screened out.