Study On The Synthetic Method Of 2,4-disubstituted-1,2,3-triazoles And Their Antitumor Activity

1,2,3-triazole is an interesting moiety, which plays an important role in biological activity. In recent years, many efforts have been paid to develop 1,2,3-triazole derivatives on the basis of many lead compounds with various pharmacological activities, and quite a few successful examples have been seen. Unfortunately, in contrast with 1,2,4-triazole, 1,2,3-triazole has only a few ways to be prepared. In most cases, 1,3-dipolar cycloaddition of azides with acetylenes is the only way to synthesize substituted 1,2,3-triazoles. In order to put more 1,2,3-triazole derivatives under the study of their biological activities, it is necessary to further its preparation methods and find an easy way to get it.In our work, as a preliminary experiment, the N-phenacylisoquinolinium bromide was reacted with methlhydrazine in refluxed acetic acid. Unexpectedly, 2-methyl-1,2,3-triazole was obtained. The further study of this reaction led to a more simple starting material, α-bromoacetophenone to react with methylhydrazine, obtaining the same product. And a more plausible reaction condition resulted a satisfactory yield of 60%. Under that optimized condition, a series of substituted α-bromoacetophenones were put to the reaction with methylhydrazine, and 11 more 2-methyl-4-ary-1,2,3-triazoles were obtained. None of them have been reported before. Some efforts were also made to find cupric ion as the right catayzer which could promote thecyclization of phenylhydrazine and a-bromoacetophenone efficiently. The optimized condition was decided by uniform design, leading to an improved yield of 50%. And it was put into application of some substituted phenylhydrazines to the reaction with a-bromoacetophenones, 30 more 2,4-diary-l,2,3-triazoles were obtained with 28 of them being new compounds. Therefore, a new way to the synthesis of 2,4-disubstituted -1,2,3-triazoles was found.The reaction mechanism was proposed here. In methylhydrazine case, a series of nucleophilic attacks of methylhydrazine to a-bromoacetophenone gave rise to an active intermediate, methylhydrazone, and it could convert to triazole immediately. While in phenylhydrazine case, the intermediate phenylhydrazone was not active enough for the reaction of intermolecular condensation, unless in the presence of oxidizer, such as cupric chloride.All of these compounds were evaluated for their inhibitory activity on human mammary cancer in Bcap 37 cell cultures, human ovariocarcinoma in HO-8910 cell cultures and human hepatocarcinoma in BEL-7402 cell cultures. 2-(o-methylphenyl)-4-(p-methoxyphenyl)-1,2,3-triazole proved to be the most potential compound in all three cell cultures. The structure-activity relationship was also discussed.