Discovery of new quinoxaline-2(1H)-one-based anticancer agents targeting VEGFR-2 as inhibitors: Design, synthesis, and anti-proliferative evaluation

El‐Adl, Khaled; Sakr, Helmy; Yousef, Reda G.; Mehany, Ahmed B. M.; Metwaly, Ahmed M.; Elhendawy, Mostafa A.; Radwan, Mohamed M.; ElSohly, Mahmoud A.; Abulkhair, Hamada S.; Eissa, Ibrahim H.

doi:10.1016/j.bioorg.2021.105105

Cited by 70 publications

(54 citation statements)

References 49 publications

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“…Through our trip in finding novel anticancer agents 9 , 15–21 , our research team has introduced several small molecules serving as ATP competitive inhibitors of VEGFR-2 depending on different scaffolds including, quinoxaline 1 22 , 23 , bis([1,2,4]triazolo)[4,3- a :3′,4′- c ]quinoxaline 2 24 , quinazolin-4(3 H )-one 3 25 , thieno[2,3- d ]pyrimidine 4 26 , 27 , 4-phenylphthalazine 5 28 and 5-benzylidenethiazolidine-2,4-dione 6 29 derivatives. The potency of some derivatives against the VEGFR-2 enzyme exceeded the already marketed VEGFR-2 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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

Elkady

Elwan

El-Mahdy

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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105

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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.

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Section: Introductionmentioning

confidence: 99%

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

Elkady

Elwan

El-Mahdy

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

105

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“…The docking investigation was carried out for Jusanin using MOE2014 software. The results of the docking process were then visualized using Discovery Studio 4.0 software [ 79 , 80 , 81 ] (See Supplementary Materials ).…”

Section: Methodsmentioning

confidence: 99%

Jusanin, a New Flavonoid from Artemisia commutata with an In Silico Inhibitory Potential against the SARS-CoV-2 Main Protease

et al. 2022

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A new flavonoid, Jusanin, (1) has been isolated from the aerial parts of Artemisia commutata. The chemical structure of Jusanin has been elucidated using 1D, 2D NMR, and HR-Ms spectroscopic methods to be 5,2′,4′-trihydroxy-6,7,5′-trimethoxyflavone. Being new in nature, the inhibition potential of 1 has been estimated against SARS-CoV-2 using different in silico techniques. Firstly, molecular similarity and fingerprint studies have been conducted for Jusanin against co-crystallized ligands of eight different SARS-CoV-2 essential proteins. The studies indicated the similarity between 1 and X77, the co-crystallized ligand SARS-CoV-2 main protease (PDB ID: 6W63). To confirm the obtained results, a DFT study was carried out and indicated the similarity of (total energy, HOMO, LUMO, gap energy, and dipole moment) between 1 and X77. Accordingly, molecular docking studies of 1 against the target enzyme have been achieved and showed that 1 bonded correctly in the protein’s active site with a binding energy of −19.54 Kcal/mol. Additionally, in silico ADMET in addition to the toxicity evaluation of Jusanin against seven models have been preceded and indicated the general safety and the likeness of Jusanin to be a drug. Finally, molecular dynamics simulation studies were applied to investigate the dynamic behavior of the Mpro-Jusanin complex and confirmed the correct binding at 100 ns. In addition to 1, three other metabolites have been isolated and identified to be сapillartemisin A (2), methyl-3-[S-hydroxyprenyl]-cumarate (3), and β-sitosterol (4).

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“…The docking investigation was carried out for 6-demethoxy-4'-O-capillarsine (1), tenuflorin C (2) using MOE2014 software and Discovery Studio 4.0 [72][73][74] (See the method part in Supplementary Materials).…”

Section: Docking Studiesmentioning

confidence: 99%

Isolation and In Silico Anti-SARS-CoV-2 Papain-Like Protease Potentialities of Two Rare 2-Phenoxychromone Derivatives from Artemisia spp.

et al. 2022

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Two rare 2-phenoxychromone derivatives, 6-demethoxy-4`-O-capillarsine (1) and tenuflorin C (2), were isolated from the areal parts of Artemisia commutata and A. glauca, respectively, for the first time. Being rare in nature, the inhibition potentialities of 1 and 2 against SARS-CoV-2 was investigated using multistage in silico techniques. At first, molecular similarity and fingerprint studies were conducted for 1 and 2 against co-crystallized ligands of eight different COVID-19 enzymes. The carried-out studies indicated the similarity of 1 and 2 with TTT, the co-crystallized ligand of COVID-19 Papain-Like Protease (PLP), (PDB ID: 3E9S). Therefore, molecular docking studies of 1 and 2 against the PLP were carried out and revealed correct binding inside the active site exhibiting binding energies of −18.86 and −18.37 Kcal/mol, respectively. Further, in silico ADMET in addition to toxicity evaluation of 1 and 2 against seven models indicated the general safety and the likeness of 1 and 2 to be drugs. Lastly, to authenticate the binding and to investigate the thermodynamic characters, molecular dynamics (MD) simulation studies were conducted on 1 and PLP.

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Discovery of new quinoxaline-2(1H)-one-based anticancer agents targeting VEGFR-2 as inhibitors: Design, synthesis, and anti-proliferative evaluation

Cited by 70 publications

References 49 publications

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

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

Jusanin, a New Flavonoid from Artemisia commutata with an In Silico Inhibitory Potential against the SARS-CoV-2 Main Protease

Isolation and In Silico Anti-SARS-CoV-2 Papain-Like Protease Potentialities of Two Rare 2-Phenoxychromone Derivatives from Artemisia spp.

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