Synthesis, Characterization And Properties Of1,2,4-triazine/1,2,4-triazole Derivatives Containing Benzimidazole Moiety

Research indicates that the protein-tyrosine phosphatase1B (PTP1B) has emerged as acritical regulator of multiple signaling networks involved in human disorders such as diabetes,obesity, and cancer. Among the super family of PTPs, Cdc25phosphatases aredual-specificity phosphatases which play a central role in cell cycle progression. Threeisoforms have been identified in human, namely Cdc25A, B and C. Cdc25A and B has beenobserved and are over-expressed in a wide variety of human cancers including breast, colon,cervix, lung, etc. Development of efficient and highly selective inhibitor of Cdc25B andPTP1B for treatment of cancer, diabetes and obesity has become a hot research topic. Ourwork is as follows:1. Twenty new3,6-disubstituted-1,2,4-triazine derivatives containing benzimidazole moiety(5a~5r), ten novel1,2,4-triazole derivatives containing benzimidazole moiety (6~8) andtwo intermediates (3b and4b) were designed and synthesized. The structures of the targetcompounds and new intermediate compounds were characterized by IR,1H NMR andelemental analyses.2. The newly synthesized target compounds5~8were screened for their inhibitory activityagainst Cdc25B and PTP1B phosphatase. The experimental results indicate that compounds5g and5j showed good inhibitory activities against Cdc25B, and5a,5h,5j,5r and5sexhibited potent inhibitory activities against PTP1B. Among them, compound5j havehigher inhibition for PTP1B than standard drug oleanolic acid. It is noteworthy thatcompound5j can be used as potential Cdc25B and PTP1B inhibitors [IC50=(2.16±0.27)and (0.59±0.04) M] in the treatment of cancer and diabetes. Target compounds6a~6g and7a~7b have weak inhibition for Cdc25B, and no activity for PTP1B. Target compound8has moderate inhibitory activity against Cdc25B and no activity for PTP1B.3. The anion recognize behavior of target compound8has also been studied by UV-vis,fluorescence and1H NMR spectra. The results display a high affinity and selectivitytowards F－and AcO－over other anions. Target compound8have potential application inthe detection of F－and AcO－anions.4. The results of this study is of great significance for further study. It will provide a scientificbasis for the development of new anti-cancer, anti-diabetic drugs and anion receptors.