Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 20, Pages 9299-9314Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01313
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Funding
- Natural Science Foundation of China [21572003, 21472025, 21877015, 81972040]
- Opening Project of Shanghai Key Laboratory of New Drug Design [SKLNDD-KF-201704]
- Natural Science Research Program of Anhui Educational Committee [KJ2019A0232]
- Scientific Research Grants of Anhui Medical University [XJ201627]
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In order to discover novel hypoxia-inducible factor 1 (HIF-1) inhibitors for the cancer metastasis treatment, 68 new aryl carboxamide compounds were synthesized and evaluated for their inhibitory effect by dual luciferase-reporter assay. Based on five rounds of investigation on structure-activity relationships step by step, compound 30m was discovered as the most active inhibitor (IC50 = 0.32 mu M) with no obvious cytotoxicity (CC50 > 50 mu M). It effectively attenuated hypoxia-induced HIF-1 alpha protein accumulation and reduced transcription of vascular epidermal growth factor in a dose-dependent manner, which was further demonstrated by its inhibitory potency on capillary-like tube formation, angiogenesis of zebrafish as well as cellular migration and invasion. Importantly, compound 30m exhibited antimetastatic potency in breast cancer lung metastasis in the mice model, indicating its promising therapeutic potential for prevention and treatment of tumor metastasis. These results definitely merit attention for further rational design of more efficient HIF-1 inhibitors in the future.
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