Vatalanib succinate

In our attempts to improve pharmacokinetics and pharmacodynamics characters of vatalanib, four strategies of the drug design were applied to design and synthesis new quinoxaline based vatalanib analogs.Antiproliferative activities of the synthesized compounds were investigated against two tumor cell lines (HepG2 and HCT-116) using vatalanib as a pos. control.The new candidates showed promising anticancer activity against two tested cancer cell lines with IC₅₀ values ranging from 6.04 ± 0.19 to 100.15 ± 3.26 μM, in particular compounds 11b and 11c which were more potent than vatalanib.The most potent was the 4-benzoylquinoxaline derivative 11b (IC₅₀ = 6.04 ± 0.19 μM and 15.58 ± 0.58 μM) compared to vatalanib (IC₅₀ of 25.27 ± 0.84 μM and 43.91 ± 1.64 μM) against HepG2 and HCT116, resp.The selectivity indexes of 11b were found to be approx. 14 and 5 towards HepG2 and HCT116, resp.While vatalanib showed selectivity indexes of about 5 and 3 towards HepG2 and HCT116, resp.The most promising compound 11b was further investigated in HepG-2 cells for its apoptotic effect, cell cycle arrest and in vitro VEGFR-2 inhibitory activity as the main mechanisms of cell death.It was found that 11b can induce apoptosis and arrest the cell cycle at the at G1 phase in addition to, compound 11b showed effective inhibition of VEGFR-2 with IC₅₀ of 0.918 ± 0.033 μM compared to vatalanib (IC₅₀ of 0.265 ± 0.009 μM).Deep computational studies were created for the designed compounds including mol. docking, physicochem. properties, profiling pharmacokinetics, ADMET studies, and toxicity predictions to evaluate the prospective drug candidates.The results of the docking study were consistent with biol. testing, furthermore, in silico ADMET study revealed the superior pharmacokinetics characters of the new candidates over vatalanib.So, the current work suggests that the 4-benzoylquinoxaline-1-yl-acetamide derivatives, especially 11b, can serve as lead mols. for development of new effective anticancer drugs.

Three new acylphloroglucinols were isolated from the branches and leaves of Hypericum perforatum L., named as hyperipersions A-C (1-3), together with three known compounds which were identified as elegaphenone (4), 2,6-dihydroxy-3,4-dimethylbenzoic acid methyl ester (5) and 2,3-methylenedioxyxanthone (6), respectively. The structures of isolated compounds were determined by UV, IR, HR-ESI-MS, NMR analysis. Their antiangiogenic activities were studied against HUVECs. The IC₅₀ value of compound 3 was 2.39 ± 0.21 μM against HUVECs, which was stronger than vatalanib, and other compounds had moderate antiangiogenic activity.