Zhang Lin-Hao, Zhang Zhi-Hong, Li Ming-Yue, Wei Zhi-Yu, Jin Xue-Jun, Piao Hu-Ri
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanji 133002, China.
Medical College of Dalian University, Dalian, Liaoning Province, 116622, China.
Bioorg Med Chem Lett. 2019 Jun 15;29(12):1440-1445. doi: 10.1016/j.bmcl.2019.04.028. Epub 2019 Apr 17.
The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of cancers. Here, we designed and synthesized 31 ursolic acid (UA) derivatives containing a tetrazole moiety and evaluated them for their potential anti-tumor activities as HIF-1α transcriptional inhibitors. Of these, compound 14d (IC 0.8 ± 0.2 µM) displayed the most potent activity and compounds 14a (IC 4.7 ± 0.2 µM) exhibited the most promising biological profile. Analysis of the structure-activity relationships of these compounds with HIF-1α suggested that the presence of a tetrazole group located at C-28 of the UA derivatives was critical for their inhibitory activities.
缺氧诱导因子-1α（HIF-1α）信号通路与肿瘤血管生成、生长和转移有关。因此，抑制该信号通路是治疗各类癌症的重要治疗靶点。在此，我们设计并合成了31种含有四氮唑部分的熊果酸（UA）衍生物，并评估了它们作为HIF-1α转录抑制剂的潜在抗肿瘤活性。其中，化合物14d（IC 0.8±0.2µM）表现出最强的活性，化合物14a（IC 4.7±0.2µM）展现出最有前景的生物学特性。对这些化合物与HIF-1α的构效关系分析表明，位于UA衍生物C-28位的四氮唑基团的存在对其抑制活性至关重要。
