新型含嘧啶环吲唑衍生物的合成及初步生物活性研究  

Synthesis and preliminary bioactivities evaluation of novel indazole derivatives containing pyrimidine

作　　者：张晓凯[1,2] 刘登科[1] 刘冰妮[1] 刘默[1] 王平保[1,2] 

机构地区：[1]天津药物研究院天津市新药设计与发现重点实验室,天津300193 [2]河南大学药学院,河南开封475000

出　　处：《中国药物化学杂志》2013年第1期15-20,共6页Chinese Journal of Medicinal Chemistry

基　　金：十二五国家重大新药创制科技重大专项(2011ZX09401-009)

摘　　要：目的设计合成新型含嘧啶环的吲唑衍生物,并检测其对VEGFR-2酶的抑制活性。方法以3-甲基-6-硝基吲唑为起始原料,经N-甲基化、氢化还原、亲核取代、烷基化及亲核取代反应合成目标化合物;采用均相时间分辨荧光(HTRF)法测定目标化合物对VEGFR-2磷酸化的抑制作用。结果与结论合成了15个未见文献报道的新化合物,其结构经1H-NMR和MS谱确证。活性评价结果显示,该系列化合物对VEGFR-2酶均有抑制活性,其中化合物7a、7c、7i表现出较强的抑制活性,其抑制活性与阳性对照药帕唑帕尼接近,由此推测此类化合物可能具有潜在的抗肿瘤活性。Based on the good antitumor activities of indazole derivatives, associated with mechanism of inhi- bition the vascular endothelial growth factor receptor（ VEGFR）, fifteen novel compounds of indazole deriva- tives were designed and synthesized by a five-step procedure including N-methylation, hydrogenation, nucle- ophilic-substitution, alkylation and SNAr reaction from 3-methyl-6-nitro-lH-indazole. Moreover the structures of these compounds were confirmed by 1H-NMR and MS. Biological activities of the compounds were detec- ted in vitro by observing their inhibition effects on phosphorylation of vascular endothelial growth factor re- ceptor. The data showed that some compounds exhibited better biological activities, such as 7a, 7c, and 7i with the inhibitory rates of 95.1%, 86. 7% and 77.2%, respectively. The inhibition percentages of some compounds were close to the value of the positive drug pazopanib. It suggests that the new structures have potential antitumor activities.

关 键 词：新型吲唑衍生物 血管内皮生长因子受体-2 合成 生物活性 

分 类 号：O626.41[理学—有机化学]