New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies

Abstract

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.

Design, Synthesis, Docking, DFT, MD Simulation Studies of a New Nicotinamide-Based Derivative: In Vitro Anticancer and VEGFR-2 Inhibitory Effects

“…The molecular docking was conducted for compound 10 against VEGFR-2 [ 34 , 35 ] by MOE2014 software (Montreal, QC, Canada). Supplementary Materials provide a thorough explanation.…”

Benzoxazole derivatives as new VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, and antiproliferative evaluation

“…The assay was applied by ELISA kits in accordance with the comprehensive description in 18 , 33 as described in Supplementary data .…”

“…These previously mentioned parts enabled the designed compounds to fit perfectly in the TK active pocket. Based on the promising biological results in our former published work in which we utilised benzoxazole moieties as a hinge-binding core 18 , we decided to continue our preliminary VEGFR-2 studies using the same three different scaffolds of benzoxazole but with two main considerable additional modifications; a) For the allosteric hydrophobic pocket, we used different terminal aliphatic hydrophobic moieties including cyclopentyl (compounds 12a-c ) and ter-butyl moiety (compounds 12d-f ). This allowed us to make a comparative study between aliphatic and aromatic derivatives of each scaffold and study the SAR of the obtained compounds as anticancer leads with significant VEGFR-2 inhibitory potentialities, as was planned in our design.…”

Multi-Step In Silico Discovery of Natural Drugs against COVID-19 Targeting Main Protease

“…Docking studies were proceeded to inspect the binding free energies (∆G) and the binding modes [111][112][113][114][115][116] of the antiviral compounds against M pro PDB ID: 6LU7 (Table 4) with PRD_002214 as a reference. Eight compounds (128, 130, 156, 180, 184, 203, 204, and 278) exhibited the most a-like binding mode and the highest binding energies.…”