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.
出处
《中国药物化学杂志》
CAS
CSCD
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)
