Synthesis, biological evaluation, and molecular docking of new series of antitumor and apoptosis inducers designed as VEGFR-2 inhibitors

Abstract

Based on quinazoline, quinoxaline, and nitrobenzene scaffolds and on pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesised. VEGFR-2 IC 50 values ranged from 60.00 to 123.85 nM for the new derivatives compared to 54.00 nM for sorafenib. Compounds 15 a , 15 b , and 15 d showed IC 50 from 17.39 to 47.10 µM against human cancer cell lines; hepatocellular carcinoma (HepG2), prostate cancer (PC3), and breast cancer (MCF-7). Meanwhile, the first in terms of VEGFR-2 inhibition was compound 15 d which came second with regard to antitumor assay with IC 50 = 24.10, 40.90, and 33.40 µM against aforementioned cell lines, respectively. Furthermore, Compound 15 d increased apoptosis rate of HepG2 from 1.20 to 12.46% as it significantly increased levels of Caspase-3, BAX, and P53 from 49.6274, 40.62, and 42.84 to 561.427, 395.04, and 415.027 pg/mL, respectively. Moreover, 15 d showed IC 50 of 253 and 381 nM against HER2 and FGFR, respectively.

New [1,2,4]triazolo[4,3‐c]quinazoline derivatives as vascular endothelial growth factor receptor‐2 inhibitors and apoptosis inducers: Design, synthesis, docking, and antiproliferative evaluation

“…The obtained low value of root mean square deviation (RMSD = 0.559) between the native and redocked pose, in addition to the symmetrical superimposition in orientation between both the native (turquoise) and redocked (magenta) co‐crystallized poses in Figure 7, guaranteed the valid performance of the docking protocol, in addition to the docking algorithm's capability to obtain the reported binding mode of sorafenib via binding with Cys917 in the hinge region and Glu883 and Asp1044 in the DFG‐binding domain (Figure 8). [ 46,54 ]…”

“…to the docking algorithm's capability to obtain the reported binding mode of sorafenib via binding with Cys917 in the hinge region and Glu883 and Asp1044 in the DFG-binding domain (Figure 8). [46,54] The docking results demonstrated that the synthesized compounds were able to detect the VEGFR-2 kinase ATP binding site and interact with the critical amino acids in the same way that sorafenib does. The binding free energies are summarized in Table 6.…”

Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

“…Nonselective chemotherapeutic agents are known to cause severe side effects [ 9 ]. Meanwhile, cancer cells differ from normal cells in their specific biochemical abnormalities [ 10 ]. The anticancer agents that have been designed to treat such abnormalities are more likely to be potent and more selective.…”

Anti-cancer and immunomodulatory evaluation of new nicotinamide derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: in vitro and in silico studies

“…Cancer cells are characterised by biochemical anomalies. Cancer cells need more oxygen and supplements to outlive and multiply; consequently, they must be close to blood vessels to have availability to the blood circulation system 3 . Angiogenesis, the growth of new blood vessels from pre-existing vasculatures, is a fundamental factor in cancer development 4 .…”