1,3-取代吲唑类低氧诱导因子l抑制剂的设计合成及其抗肝癌活性

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(IC₅₀)值为10.37 μmol/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。

Synthesis and Anti-Hepatoma Activities of 1,3-Substituted Indazole Derivatives as Hypoxia Induced Factor Inhibitors

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(IC₅₀) values of 10.37 μmol/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.