Design, synthesis and biological evaluation of [1,2,3]triazolo[4,5-d]pyrimidine derivatives possessing a hydrazone moiety as antiproliferative agents

• DOI: 10.1016/j.ejmech.2016.10.022
• Publication Date: 2016-10-17T05:12:48Z
• Authors: Zhong-Hua Li; Dong-Xiao Yang; Peng-Fei Geng; Ji Zhang; Hao-Ming Wei; Biao Hu; Qian Guo; Xin-Hui Zhang; Wen-Ge Guo; Bing Zhao; Bin Yu; Li-Ying Ma; Hong-Min Liu
• Keywords: Histone Demethylases; Membrane Potential, Mitochondrial; 0301 basic medicine; 0303 health sciences; Hydrazones; Antineoplastic Agents; Apoptosis; Chemistry Techniques, Synthetic; Triazoles; Up-Regulation; 3. Good health; Structure-Activity Relationship; 03 medical and health sciences; Pyrimidines; Cell Line, Tumor; Drug Design; Humans; Drug Screening Assays, Antitumor; Cell Proliferation

A series of [1,2,3]triazolo[4,5-d]pyrimidine derivatives bearing a hydrazone moiety were designed, synthesized and evaluated for their antiproliferative activity against several cancer cell lines of different origins by MTT assay. Most of the synthesized compounds demonstrated moderate to good activity against the cancer cell lines selected. Especially, compound 43 showed the most potent antiproliferative activity as well as good selectivity between cancer and normal cells (IC50 values of 0.85 μM against MGC-803 and 56.17 μM against GES-1). In addition, compound 43 evidently inhibited the colony formation of MGC-803 cells at 0.8 μM. Further mechanism studies revealed that compound 43 could induce apoptosis of MGC-803 cells probably through the mitochondrial pathway accompanied with decrease of the mitochondrial membrane potential (MMP), activations of caspase-9/3, up-regulation of the expression of Bax, Bak and PUMA, as well as down-regulation of that of Bcl-2 and Mcl-1.