标题：Synthesis of Novel Pyrazole Derivatives and Their Tumor Cell Growth Inhibitory Activity
作者：Cui, Ying-Jie; Tang, Long-Qian; Zhang, Cheng-Mei; Liu, Zhao-Peng
作者机构：[Cui, Ying-Jie; Tang, Long-Qian; Zhang, Cheng-Mei; Liu, Zhao-Peng] Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Inst Med Chem,Key Lab Chem Biol, Ji 更多
通讯作者地址：[Liu, ZP]Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Inst Med Chem,Key Lab Chem Biol, Jinan 250012, Shandong, Peoples R China.
关键词：privileged structure; pyrazoles; tubulin inhibitors; antitumor;; antitumor agents
摘要：To find novel antitumor agents, a series of 1H-benzofuro[3,2-c]pyrazole derivatives 4a-e were designed and synthesized. The treatment of 6-methoxybenzofuran-3(2H)-one 3 with LiHMDS in anhydrous tetrahydrofuran (THF) followed by reaction with 3-substitued phenyl isothiocyanate gave the thioamide intermediates, which underwent condensation with hydrazine monohydrate in dioxane/EtOH (1:1) to provide the benzofuropyrazole derivatives 4a-e as well as the unexpected pyrazole derivatives 5a-e. In tumor cell growth inhibitory assay, all the benzofuropyrazole derivatives were not active against the breast tumor MCF-7 cell, only 4a was highly active and more potent than ABT-751 against the leukemia K562 (GI(50) = 0.26 M) and lung tumor A549 cells (GI(50) = 0.19 M), while other benzofuropyrazoles showed very weak inhibitory activity. In contrast, the pyrazoles 5a-e were in general more potent than the benzofuropyrazoles 4a-e. Compound 5a exhibited a similar tendency to that of 4a with high potency against K562 and A549 cells but weak effects on MCF-7 cell. Both pyrazoles 5b and 5e exhibited high inhibitory activities against K562, MCF-7 and A549 cells. The most active compound 5b was much more potent than ABT-751 against K562 and A549 cells with GI(50) values of 0.021 and 0.69 M, respectively. Moreover, 5b was identified as a novel tubulin polymerization inhibitor with an IC50 of 7.30 M.