AI Summary
The article discusses the discovery of new 1,3-diphenylurea appended aryl pyridine derivatives that act as apoptosis inducers by inhibiting c-MET and VEGFR-2. These compounds showed potent IC50 values against these receptors as well as exhibited cytotoxicity against MCF-7 and PC-3 cancer cells. Compound 2n in particular induced significant cell death in MCF-7 cells, affecting apoptosis-related genes. In vivo studies demonstrated the anticancer activity of compound 2n against breast cancer, showing a reduction in tumor mass and volume and an improvement in hematological parameters. The findings suggest that compound 2n could be further developed as a selective targeted chemotherapeutic agent for breast cancer.
Interest has been generated in VEGFR-2 and c-MET as potential receptors for the treatment of different malignancies. Using aryl pyridine derivatives with 1,3-diphenylurea attached, a number of promising dual VEGFR-2 and c-MET inhibitors were developed and synthesized. Regarding the molecular target, compounds 2d, 2f, 2j, 2k, and 2n had potent IC50 values of 65, 24, 150, 170, and 18 nM against c-MET, respectively. Additionally, had potent IC50 values of 310, 35, 290, 320, and 24 nM, respectively against VEGFR-2, respectively. For cytotoxicity, compounds 2d, 2f, 2j, 2k and 2n exhibited potent cytotoxicity against MCF-7 with IC50 values range (0.76-21.5 μM), and they showed promising cytotoxic activity against PC-3 with IC50 values range (1.85-3.42 μM) compared to Cabozantinib (IC50 = 1.06 μM → MCF-7 and 2.01 μM → PC-3). For the cell death, compound 2n caused cell death in MCF-7 cells by 87.34-fold; it induced total apoptosis by 33.19% (8.04 % for late apoptosis, 25.15% for early apoptosis), stopping their growth in phase G2/M affecting the expression of apoptosis-related genes of P53, Bax, caspases 3, 9 and the anti-apoptotic gene, Bcl-2. In vivo study illustrated the anticancer activity of compound 2n by reduction of tumor mass and volume, and the tumor inhibition ratio reached 56.1% with an improvement of hematological parameters. Accordingly, compound 2n can be further developed as a selective target-oriented chemotherapeutics against breast cancer.