Synthesis and biological evaluation of 1-(4-(7-hydroxy-4-oxo-4H-chromen-3-yl)phenyl)-3-arylurea derivtives as anti-tumor modulators targeting Nur77

Abstract

As part of our ongoing work on anti-tumor Nur77 modulators, a series of novel 1-(4-(7‑hydroxy-4-oxo-4H-chromen-3-yl)phenyl)-3-arylurea derivatives 7a–7p were designed and synthesized in six steps. All compounds were characterized by ¹HNMR, ¹³CNMR, and high-resolution mass spectrometry (HRMS). Their anti-proliferation activities against HepG2 and MCF-7 cells were evaluated in vitro. Among these, compound 7k showed significant inhibitory activity against HepG2 and MCF-7 cells with IC₅₀ values of 3.93 ± 0.54 μM and 4.75 ± 0.48 μM respectively, the IC₅₀ value of normal liver cell L-O2 is greater than 50 μM, SI > 12.7. Nur77, an orphan nuclear receptor with diverse biological functions, was identified as a direct binding target of compound 7k, as suggested by molecular docking studies. Moreover, 7k also upregulated the protein level of Nur77 in a time/dose-dependent manner. The results of colony formation and scratch assay also showed that 7k inhibited the proliferation and migration of HepG2. Additionally, 7k induced PARP cleavage and increased the protein levels of BAX and activated caspase 3. In conclusion, 7k exerts anticancer effects by inhibiting proliferation and inducing apoptosis in HepG2 cells.