ALBERT

Description: 〈p〉Publication date: Available online 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Eman Y. Ahmed, Nehad A. Abdel Latif, Mohamed F. El-Mansy, Weam S. Elserwy, Omaima M. Abdelhafez〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Twenty five newly synthesized coumarin scaffold based derivatives were assayed for their 〈em〉in vitro〈/em〉 anticancer activity against MCF-7 breast and PC-3 prostate cancer cell lines and were further assessed for their 〈em〉in vitro〈/em〉 VEGFR-2 kinase inhibitory activity. The 〈em〉in vitro〈/em〉 cytotoxic studies revealed that most of the synthesized compounds possessed very promising cytotoxicity against MCF-7, particularly; compounds 〈strong〉4a〈/strong〉 (IC〈sub〉50〈/sub〉 = 1.24 µM) and 〈strong〉3d〈/strong〉 (IC〈sub〉50〈/sub〉 = 1.65 µM) exhibited exceptional activities superior to the positive control staurosporine (IC〈sub〉50〈/sub〉 = 8.81 µM). Similarly, the majority of the compounds exhibited higher antiproliferative activities compared to the reference standard with IC〈sub〉50〈/sub〉 values ranging from 2.07 to 8.68 µM. The two cytotoxic derivatives 〈strong〉4a〈/strong〉 and 〈strong〉3d〈/strong〉 were selected to evaluate their inhibitory potencies against VEGFR-2 kinase. Remarkably, compound 〈strong〉4a,〈/strong〉 exhibited significant IC〈sub〉50〈/sub〉 of 0.36 µM comparable to staurosporine (IC〈sub〉50〈/sub〉; 0.33 µM). Moreover, it was capable of inducing preG1 apoptosis, cell growth arrest at G2/M phase and activating caspase-9. On the other hand, insignificant cytotoxic activity was observed for all compounds towards PC-3 cell line. Molecular docking study was carried out for the most active anti-VEGFR-2 derivative 〈strong〉4a,〈/strong〉 which demonstrated the ability of the tested compound to interact with the key amino acids in the target VEGFR-2 kinase binding site〈strong〉.〈/strong〉 Additionally, the ADME parameters and physicochemical properties of compound 〈strong〉4a〈/strong〉 were examined 〈em〉in silico〈/em〉.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619313549-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉