摘要
低氧诱导因子l(HIF-1)与肿瘤细胞的生长、侵袭和耐药密切相关,在肿瘤细胞内HIF-1高度表达,因此新型的HIF-1抑制剂可作为潜在的抗肿瘤药物。本文合成了9个1,3-取代吲唑衍生物。通过蛋白质印迹(Western Blot)法及实时定量荧光PCR(Real time-PCR)等方法检测了其对HIF-1及其靶基因血管内皮生长因子(VEGF)表达水平的影响,并以3-(5'-羟甲基-2'-呋喃基)-1-苯甲基吲唑(YC-1)为阳性对照药物初步评价了其体外抗肝癌细胞增殖的生物活性。实验发现化合物7b可显著抑制HIF-1及其下游靶基因VEGF的表达,且体外抗肝癌增殖生物活性优于YC-1,半抑制浓度(IC_(50))值为10.37μmol/L。研究结果表明,3-(5'-羟甲基-2'-呋喃)-1-(1″-对甲苯磺酰基)吲唑具有靶向抑制HIF及良好的抗肝癌活性作用。
Hypoxia-inducible factor 1(HIF-1)is closely related to the growth,invasion and drug resistance of tumor cells and is highly expressed in tumor cells,so new HIF-1 inhibitors can be used as potential antitumor drugs.Nine 1,3-substituted indazole derivatives were synthesized.The expression of HIF-1 and its target gene vascular endothelial growth factor(VEGF)were detected by Western Blot and Real time-PCR(polymerase chain reaction),and the anti-tumor activities of all the newly synthesized compounds were evaluated on the in vitro growth of HepG2 cell line taking 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole(YC-1)(compound 7d)as positive control.We found that compound 7b significantly inhibited the expression of HIF-1 and its downstream target gene VEGF,and the anti-hepatoma biological activity in vitro of compound 7b was better than that of YC-1 with half maximal inhibitory concentration(IC 50)values of 10.37μmol/L.The results show that 3-(5′-hydroxy methyl-2′-furan)-1-(1′-p-tolylsulfonyl)indazole targets the inhibition of HIF activity,but also has a good anti-hepatoma activity.
作者
李善花
黄志宁
苗方笑
郑满意
梁涵
王宝睿
曲宁
乔红
王海莉
李福男
LI Shanhua;HUANG Zhining;MIAO Fangxiao;ZHENG Manyi;LIANG Han;WANG Baorui;QU Ning;QIAO Hong;WANG Haili;LI Funan(Medical College,Xiamen University,Xiamen,Fujian 361102,China;School of Pharmaceutical Sciences,Xiamen University,Xiamen,Fujian 361102,China)
出处
《应用化学》
CAS
CSCD
北大核心
2018年第4期410-419,共10页
Chinese Journal of Applied Chemistry
基金
福建省科技厅项目(2015Y0081
2015J01350)
厦门大学大学生创新创业训练计划项目(2016X0644
20720152005)~~
