Study On Synthesis And Antitumor Activities Of Benzotriazole Derivatives

Protein tyrosine kinase(PTK) inhibitor is one of the new targets of oncotherapy. The epidermal growth factor receptor(EGFR) and the vascularendothelial growth factor receptor (VEGFR) are the most remarkable members of PTK, which are closely related to the latest cancer treatment strategy—anti-angiogenesis therapy. The main PTK inhibitors used in clinical is 4-oxacillin quinoline derivatives. The desired benzotriazolylprop-2-enenitriles was designed by applying the principles of bioisosterism and twin drug . With Axitinib as a leading compound, benzotriazole ring replaces indazole ring of Axitinib and is connected with another pharmacophore (pyridine, 2- pyridyl,3- pyridyl,4- pyridyl) by C=C. These new chemical entities (NCE) are belong to analog drug.The main work of this paper:1. 2-(1H-Benzotriazol-1-yl)acetonitrile ( B1 ) and 2-(2H-Benzotriazol-2-yl) acetonitrile ( B2 ) were synthesized with the reaction of Benzotriazole and chloroacetonitrile in different temperature and acid binging agent. The products were characterized by IR, 1HNMR and MS. The results showed that the yield of 2-(1H-Benzotriazol-1-yl)acetonitrile (B1)and 2-(2H-Benzotriazol-2-yl) acetonitrile (B2)was correlated with the deprotonation ability of acid binging agent. Under the same temperature the order of activity was K2CO3/ethyl acetate > KF/DMF > (C2H5)3N/DMF. The total yield of the target product was 88.51% with anhydrous K2CO3 as acid binging agent in ethyl acetate at 100℃.By a large number of experiments to explore the reaction conditions,the synthesis process was optimized.2. Five novel desired benzotriazolylprop-2-enenitriles were synthesized with the reaction of 2-(1H-Benzotriazol-1-yl)acetonitrile (B1)or 2-(2H-Benzotriazol-2- yl) acetonitril(eB2) with pyridine-2-aldehyde, pyridine-3-aldehyde, pyridine-4-aldehyde respectively. The structures of the target compounds were characterized by IR and 1H-NMR.3. The antitumor activity of five novel benzotriazolylprop-2-enenitriles was determined by MTT assay. The results showed that benzotriazole derivatives suppressed proliferation of PANC-1,K562,ASPC-1 cells in a dose-dependent manner. The inhibiting rate of [2-(1H-benzotriazol-1-yl)-3-(2-pyridine)]acrylonitriles(B1P2) on K562 PANC-1,ASPC-1 cell was the highest with IC50 0.38μg/mL, 1.04μg/mL,0.57μg/mL, which could be used as research emphasis to further development of this kind compounds.