| Summary: | This work is one of our efforts to discover potent anticancer agents. We modified the most promising derivative of our previous work concerned with the development of VEGFR-2 inhibitor candidates. Thirteen new compounds based on benzoxazole moiety were synthesized and evaluated against three human cancer cell lines, namely, breast cancer (MCF-7), colorectal carcinoma (HCT116), and hepatocellular carcinoma (HepG2). The synthesized compounds were also evaluated against VEGFR-2 kinase activity. The biological testing fallouts showed that compound <b>8d</b> was more potent than standard sorafenib. Such compound showed IC<sub>50</sub> values of 3.43, 2.79, and 2.43 µM against the aforementioned cancer cell lines, respectively, compared to IC<sub>50</sub> values of 4.21, 5.30, and 3.40 µM reported for sorafenib. Compound <b>8d</b> also was found to exert exceptional VEGFR-2 inhibition activity with an IC<sub>50</sub> value of 0.0554 μM compared to sorafenib (0.0782 μM). In addition, compound <b>8h</b> revealed excellent cytotoxic effects with IC<sub>50</sub> values of 3.53, 2.94, and 2.76 µM against experienced cell lines, respectively. Furthermore, compounds <b>8a</b> and <b>8e</b> were found to inhibit VEGFR-2 kinase activity with IC<sub>50</sub> values of 0.0579 and 0.0741 μM, exceeding that of sorafenib. Compound <b>8d</b> showed a significant apoptotic effect and arrested the HepG2 cells at the pre-G1 phase. In addition, it exerted a significant inhibition for TNF-α (90.54%) and of IL-6 (92.19%) compared to dexamethasone (93.15%). The molecular docking studies showed that the binding pattern of the new compounds to VEGFR-2 kinase was similar to that of sorafenib.
|
|---|