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A new series of benzoxazole derivatives were designed and synthesised to have the main essential pharmacophoric features of VEGFR-2 inhibitors. Cytotoxic activities were evaluated for all derivatives against two human cancer cell lines, MCF-7 and HepG2. Also, the effect of the most cytotoxic derivatives on VEGFR-2 protein concentration was assessed by ELISA. Compounds 14o , 14l , and 14b showed the highest activities with VEGFR-2 protein concentrations of 586.3, 636.2, and 705.7 pg/ml, respectively. Additionally, the anti-angiogenic property of compound 14b against human umbilical vascular endothelial cell (HUVEC) was performed using a wound healing migration assay. Compound 14b reduced proliferation and migratory potential of HUVEC cells. Furthermore, compound 14b was subjected to further biological investigations including cell cycle and apoptosis analyses. Compound 14b arrested the HepG2 cell growth at the Pre-G1 phase and induced apoptosis by 16.52%, compared to 0.67% in the control (HepG2) cells. The effect of apoptosis was buttressed by a 4.8-fold increase in caspase-3 level compared to the control cells. Besides, different in silico docking studies were also performed to get better insights into the possible binding mode of the target compounds with VEGFR-2 active sites.

Herein, a new wave of bis([1, 2, 4]triazolo)[4,3- a :3',4'- c ]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a , 23i , 23j , 23l , and 23n displayed the highest antiproliferative activities against the two cell lines with IC 50 values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a , 23d , 23h , 23i , 23j , 23l , 23 m , and 23n showed the highest VEGFR-2 inhibitory activities with IC 50 values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC 50 = 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).

Tumor angiogenesis is mainly regulated by VEGFR-2. In this study, a new series of [1,2,4]triazolo[4,3-a]quinoxaline based-derivatives has been designed and synthesized to develop new anti-proliferative and anti-VEGFR-2 members. Anti-proliferative activities of the synthesized compounds were tested against MCF-7 and HepG2 cell lines. Compound 19a exhibited the highest activity towards both MCF-7 and HepG2 cell lines (IC 50  = 8.2 and 5.4 µM, respectively), compared to sorafenib (IC 50  = 3.51 and 2.17 µM, respectively). Additionally, all compounds were screened to evaluate their effect as VEGFR-2 inhibitors. Compound 19a (IC 50  = 3.4 nM) exhibited good activity compared to sorafenib (IC 50  = 3.12 nM). Furthermore, compound 19a disrupted the HepG2 cell cycle by arresting the G2/M phase. Also, marked increase in the percentage apoptotic cells was achieved by compound 19a. The induced apoptotic effect of compound 19a in HepG2 cells was assured by increased pro-apoptotic marker (Bax) expression by 2.33-fold and decreased anti-apoptotic (Bcl-2) expression by 1.88-fold, resulting in an elevation of the Bax/Bcl-2 ratio in HepG2 cells. Comparing to the control cells, compound 19a induced an increase in expression of cleaved caspase-3 and caspase-9 by 2.44- and 2.69-fold, respectively. Finally, the binding modes of the target derivatives were investigated through docking studies against the proposed molecular target (VEGFR-2, PDB ID: 2OH4)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). These compounds were synthesized and evaluated for their in vitro cytotoxic activities against a panel of four human tumor cell lines, namely colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), breast cancer (MCF-7), and non-small cell lung cancer cells (A549). Five of the synthesized compounds, 11a, 11b, 12b, 15b and 16a, were found to exhibit moderate antiproliferative activity against the tested cell lines and were more active than the EGFR inhibitor erlotinib. In particular, compound 11b showed 4.5- to 8.4-fold erlotinib activity against HCT-116, HepG-2, MCF-7, and A549 cells with IC50 values of 3.37, 3.04, 4.14, and 2.4 μM respectively. Moreover, the most cytotoxic compounds that showed promising IC50 values against the four cancer cell lines were subjected to further investigation for their kinase inhibitory activities against EGFRWT and EGFRT790M using homogeneous time resolved fluorescence (HTRF) assay. Compound 11b was also found to be the most active compound against both EGFRWT and mutant EGFRT790M, exhibiting IC50 values of 0.09 and 4.03 μM, respectively. The cell cycle and apoptosis analyses revealed that compound 11b can arrest the cell cycle at the G2/M phase and induce significant apoptotic effects in HCT-116, HepG-2, and MCF-7 cells. Additionally, compound 11b upregulated the level of caspase-3 by 6.5 fold in HepG-2 when compared with the control. Finally, molecular docking studies were carried out to examine the binding mode of the synthesized compounds against the proposed targets; EGFRWT and EGFRT790M. Additional in silico ADMET studies were performed to explore drug-likeness properties.