期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 29, 期 6, 页码 853-858出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.12.060
关键词
Ursolic acid; Aminoguanidine; Anticancer activity; HIF-1 alpha inhibitor; Cytotoxicity
资金
- National Science Foundation of China [81260468, 81660608, 81760657]
- Natural Science Foundation of Jilin Province [20160101218JC]
- Edanz Group China
The transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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-1 alpha inhibitors and anti-cancer agents using human cancer cell lines. Most of the compounds exhibited significant inhibition of HIF-1 alpha transcriptional activity, as measured using a Hep3B cell-based luciferase reporter assay. Among these compounds, 7b was the most potent inhibitor of HIF-1 alpha expression under hypoxic conditions (IC50 4.0 mu M) 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-1 alpha protein expression, possibly by suppressing its synthesis, reduced production of vascular endothelial growth factor, and inhibited the proliferation of cancer cells.
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