Design, synthesis and evaluation of the novel chalcone derivatives with 2,2-dimethylbenzopyran as HIF-1 inhibitors that possess anti-angiogenic potential

Hypoxia-inducible factor-1 (HIF-1) as a key mediator in tumor metastasis, angiogenesis and poor patient prognosis, has been recognized as an important cancer drug target. Up to now, some HIF-1 inhibitors with diverse skeletal structures were reported as anticancer agents, mostly natural product-derived compounds. In this study, we designed and synthesized a series of chalcone-based compounds with 2,2-dimethylbenzopyran using the combination principles to select benzopyrans and chalcones natural products. A novel series of chalconebased compounds with 2,2-dimethylbenzopyran were evaluated as HIF-1 inhibitor. HRE luciferase reporter assay demonstrated compounds showed superior HIF-1 inhibitory activity. Among them, compound 16e exhibited the best features: the strongest HIF-1 inhibitory activity (IC50 = 2.38 mu M, 3-fold higher than that of LXH-SYP-7). Meanwhile, it also significantly suppressed migration and VEGF-induced invasion of A549 cells in nontoxic concentrations. Additionally, tube formation assay demonstrated its anti-angiogenesis activity. Moreover, the in vivo study indicated that compound 16e could retard angiogenesis in the matrigel plug assay model, and almost no new blood vessels were formed in the suppository when it reached 20 mu M. Finally, we also performed a subchronic toxicity test in which doses up to 50 mg/kg were administered orally for 10 days in Kunming mice with no toxic adverse effects and were well tolerated. These findings support the further investigation on the anti-invasive and anti-angiogenic potential of this class of compounds as HIF-1 inhibitor.

Automated summary

In this study, a series of chalcone-based compounds with 2,2-dimethylbenzopyran were designed and synthesized. Compound 16e showed the strongest HIF-1 inhibitory activity, as well as significant suppression of cell migration and VEGF-induced invasion, and anti-angiogenesis activity. The compound also demonstrated no toxic adverse effects in animal tests, suggesting its potential as an anti-invasive and anti-angiogenic agent.