Discovery of Novel Aryl Carboxamide Derivatives as Hypoxia-Inducible Factor 1α Signaling Inhibitors with Potent Activities of Anticancer Metastasis

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 μM) with no obvious cytotoxicity (CC₅₀ > 50 μM). It effectively attenuated hypoxia-induced HIF-1α 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.