Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanji 133002, China.
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanji 133002, China.
Bioorg Med Chem Lett. 2019 Mar 15;29(6):853-858. doi: 10.1016/j.bmcl.2018.12.060. Epub 2018 Dec 28.
The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role in tumor angiogenesis, growth, and metastasis and is recognized as an important potential therapeutic target for cancer. Here, we designed and synthesized three novel series of ursolic acid derivatives containing an aminoguanidine moiety and evaluated them as HIF-1α inhibitors and anti-cancer agents using human cancer cell lines. Most of the compounds exhibited significant inhibition of HIF-1α transcriptional activity, as measured using a Hep3B cell-based luciferase reporter assay. Among these compounds, 7b was the most potent inhibitor of HIF-1α expression under hypoxic conditions (IC 4.0 µM) and did not display significant cytotoxicity against any cell lines tested. The mechanism of action of 7b was investigated, we found that 7b downregulated HIF-1α protein expression, possibly by suppressing its synthesis, reduced production of vascular endothelial growth factor, and inhibited the proliferation of cancer cells.
转录因子缺氧诱导因子-1α（HIF-1α）在肿瘤血管生成、生长和转移中发挥重要作用，被认为是癌症治疗的一个重要潜在靶点。在这里，我们设计并合成了含有氨基胍部分的三种新型熊果酸衍生物系列，并用人癌细胞系评估它们作为 HIF-1α 抑制剂和抗癌剂的活性。大多数化合物在 Hep3B 细胞基于荧光素酶报告基因的测定中显示出对 HIF-1α 转录活性的显著抑制。在这些化合物中，7b 在缺氧条件下对 HIF-1α 表达的抑制作用最强（IC 4.0µM），并且对测试的任何细胞系均没有明显的细胞毒性。我们研究了 7b 的作用机制，发现 7b 通过抑制其合成，降低血管内皮生长因子的产生，从而下调 HIF-1α 蛋白表达，并抑制癌细胞的增殖。
