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.