Discovery of new thiazolidine-2,4-dione derivatives as potential VEGFR-2 inhibitors: In vitro and in silico studies DOI Creative Commons
Ibrahim H. Eissa, Hazem Elkady, Mahmoud Rashed

et al.

Heliyon, Journal Year: 2024, Volume and Issue: 10(2), P. e24005 - e24005

Published: Jan. 1, 2024

In this study, a series of seven novel 2,4-dioxothiazolidine derivatives with potential anticancer and VEGFR-2 inhibiting abilities were designed synthesized as inhibitors. The compounds tested in vitro for their to inhibit the growth HepG2 MCF-7 cancer cell lines. Among tested, compound 22 (IC50 = 0.079 μM) demonstrated highest anti-VEGFR-2 efficacy. Furthermore, it significant anti-proliferative activities against 2.04 ± 0.06 1.21 0.04 M). Additionally, also increased total apoptotic rate lines cycle arrest at S phase. As well, computational methods applied study VEGFR-2-22 complex molecular level. Molecular docking dynamics (MD) simulations used investigate complex's structural kinetic characteristics. DFT calculations further revealed electronic properties 22. Finally, ADMET toxicity tests performed indicating likeness proposed be drugs. results suggest that displays promise an effective treatment can serve model future modifications biological investigations field.

Language: Английский

Angiogenic signaling pathways and anti-angiogenic therapy for cancer DOI Creative Commons

Zhenling Liu,

Huanhuan Chen,

Lili Zheng

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 11, 2023

Abstract Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- anti-angiogenic molecules, which plays crucial role in tumor growth, invasion, metastasis. With advances molecular cellular biology, biomolecules such as growth factors, chemokines, adhesion factors involved angiogenesis has gradually been elucidated. Targeted therapeutic research based on these molecules driven treatment to become promising strategy anti-tumor therapy. The most widely used agents include monoclonal antibodies tyrosine kinase inhibitors (TKIs) targeting vascular endothelial factor (VEGF) pathway. However, clinical benefit this modality still limited due several defects adverse events, acquired drug resistance, recurrence, lack validated biomarkers, impel further mechanisms angiogenesis, development multiple drugs combination therapy figure out how improve efficacy. Here, we broadly summarize signaling pathways discuss current challenges We also propose approaches efficacy provide perspective for

Language: Английский

Citations

483
New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies DOI Creative Commons
Hazem Elkady, Alaa Elwan, Hesham A. El-Mahdy

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 37(1), P. 403 - 416

Published: Dec. 27, 2021

A new series of benzoxazole derivatives were designed and synthesised to have the main essential pharmacophoric features VEGFR-2 inhibitors. Cytotoxic activities evaluated for all against two human cancer cell lines, MCF-7 HepG2. Also, effect most cytotoxic on protein concentration was assessed by ELISA. Compounds

Language: Английский

Citations

113
Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: in-vitro anticancer evaluation and in-silico studies DOI Creative Commons
Mohammed S. Taghour, Hazem Elkady, Wagdy M. Eldehna

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 1903 - 1917

Published: July 8, 2022

A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids potential activity against VEGFR-2. The cytotoxic effects of synthesised derivatives Caco-2, HepG-2, MDA-MB-231 cell lines were investigated. Compound 12a found be most potent candidate investigated IC50 values 2, 10, 40 µM, respectively. Furthermore, tested in vitro for their VEGFR-2 inhibitory showing strong inhibition. Moreover, an viability study Vero non-cancerous line results reflected a high safety profile all compounds. further its apoptotic behaviour by assessing gene expression four genes (Bcl2, Bcl-xl, TGF, Survivin). Molecular dynamic simulations authenticated affinity, accurate binding, perfect dynamics compound

Language: Английский

Citations

81
New quinoxaline-based VEGFR-2 inhibitors: design, synthesis, and antiproliferative evaluation with in silico docking, ADMET, toxicity, and DFT studies DOI Creative Commons
Mohammed M. Alanazi, Hazem Elkady, Nawaf A. Alsaif

et al.

RSC Advances, Journal Year: 2021, Volume and Issue: 11(48), P. 30315 - 30328

Published: Jan. 1, 2021

A new series of 3-methylquinoxaline-based derivatives having the same essential pharmacophoric features as VEGFR-2 inhibitors have been synthesized and evaluated for their antiproliferative activities against two human cancer cell lines, MCF-7 HepG-2. Compounds 15b 17b demonstrated a significant effect with IC50 ranging from 2.3 to 5.8 μM. An enzymatic assay was carried out all tested candidates VEGFR-2. Compound most potent inhibitor (IC50 = 2.7 nM). Mechanistic investigation including cycle arrest apoptosis performed compound HepG-2 cells, results revealed that induced arrested in G2/M phase. Moreover, analyses were conducted evaluate its apoptotic potential. The showed upregulation caspase-3 caspase-9 levels, improving Bax/Bcl-2 ratio by more than 10-fold. Docking studies determine possible interaction active site. Further docking cytochrome P450 present such compounds non-inhibitors. In silico ADMET, toxicity, physico-chemical properties members acceptable values drug-likeness. Finally, DFT calculate thermodynamic, molecular orbital electrostatic potential properties.

Language: Английский

Citations

58
New quinoline and isatin derivatives as apoptotic VEGFR-2 inhibitors: design, synthesis, anti-proliferative activity, docking, ADMET, toxicity, and MD simulation studies DOI Creative Commons
Eslam B. Elkaeed, Mohammed S. Taghour,

Hazem A. Mahdy

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 2191 - 2205

Published: Aug. 16, 2022

New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects these compounds were estimated against A549, Caco-2, HepG2, MDA-MB-231. Compounds 13 14 showed comparable activities with doxorubicin Caco-2 cells. These strongly inhibited kinase activity. cytotoxic evaluated Vero Compound 7 highest value safety selectivity. Cell migration assay displayed ability compound to prevent healing abilities in cancer Furthermore, induced apoptosis through expressive down-regulation apoptotic genes, Bcl2, Bcl-xl, Survivin, upregulation TGF gene. Molecular docking emerged interactions synthesised a similar way sorafenib. Additionally, seven molecular dynamics simulations studies applied confirmed stability active pocket over 100 ns.

Language: Английский

Citations

56
Multi-Step In Silico Discovery of Natural Drugs against COVID-19 Targeting Main Protease DOI Open Access
Eslam B. Elkaeed, Fadia S. Youssef, Ibrahim H. Eissa

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(13), P. 6912 - 6912

Published: June 21, 2022

In continuation of our antecedent work against COVID-19, three natural compounds, namely, Luteoside C (130), Kahalalide E (184), and Streptovaricin B (278) were determined as the most promising SARS-CoV-2 main protease (Mpro) inhibitors among 310 naturally originated antiviral compounds. This was performed via a multi-step in silico method. At first, molecular structure similarity study done with PRD_002214, co-crystallized ligand Mpro (PDB ID: 6LU7), favored thirty Subsequently, fingerprint respect to PRD_002214 resulted election sixteen compounds (7, 128, 130, 156, 157, 158, 180, 184, 203, 204, 210, 237, 264, 276, 277, 278). Then, results docking versus PDB 6LU7 eight (128, 278) based on their binding affinities. toxicity studies for revealed that all them have good profiles. Finally, dynamic (MD) simulation experiments carried out 278, which exhibited best modes Mpro. MD tests luteoside (130) has greatest potential inhibit protease.

Language: Английский

Citations

54
Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation DOI Creative Commons
Alaa Elwan, Abdallah E. Abdallah,

Hazem A. Mahdy

et al.

Molecules, Journal Year: 2022, Volume and Issue: 27(15), P. 5047 - 5047

Published: Aug. 8, 2022

This work is one of our efforts to discover potent anticancer agents. We modified the most promising derivative previous concerned with development VEGFR-2 inhibitor candidates. Thirteen new compounds based on benzoxazole moiety were synthesized and evaluated against three human cancer cell lines, namely, breast (MCF-7), colorectal carcinoma (HCT116), hepatocellular (HepG2). The also kinase activity. biological testing fallouts showed that compound

Language: Английский

Citations

46
The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1H-Indole Derivative: In Silico and In Vitro Approaches DOI Open Access
Eslam B. Elkaeed, Reda G. Yousef, Hazem Elkady

et al.

Processes, Journal Year: 2022, Volume and Issue: 10(7), P. 1391 - 1391

Published: July 17, 2022

Corresponding to the reported features of anti-VEGFR-2-approved compounds, a new 1H-indole derivative (compound 7) was designed. The inhibitory potential designed compound revealed via molecular docking study that showed appropriate binding. Then, MD simulation (six studies) over period 100 ns performed confirm precise binding and optimum energy. Additionally, MM-GBSA reaffirmed perfect binding, exhibiting total energy −40.38 Kcal/Mol. experiments named essential amino acids in protein–ligand interaction, employing decomposition revealing diversity interactions 7 inside VEGFR-2 enzyme. As is new, DFT were utilized for structure optimization. results validated coherent interaction with A good value drug-likeness acknowledged silico ADMET studies. Interestingly, experimental vitro prohibitory better than sorafenib, demonstrating an IC50 25 nM. Notably, strong effects 10 against two cancer cell lines (MCF-7 HCT 116) established values 12.93 11.52 μM, disclosing high selectivity indexes 6.7 7.5, respectively.

Language: Английский

Citations

45
Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies DOI Creative Commons
Reda G. Yousef,

Albaraa Ibrahim,

Mohamed M. Khalifa

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 1389 - 1403

Published: May 16, 2022

A library of modified VEGFR-2 inhibitors was designed as inhibitors. Virtual screening conducted for the hypothetical using in silico docking, ADMET, and toxicity studies. Four compounds exhibited high affinity against an acceptable range drug-likeness. These were synthesised subjected to vitro cytotoxicity assay two cancer cell lines besides inhibitory determination. Compound D-1 showed cytotoxic activity HCT-116 cells almost double that sorafenib. Compounds A-1, C-6, good IC50 values VEGFR-2. markedly increased levels caspase-8 BAX expression decreased anti-apoptotic Bcl-2 level. Additionally, compound caused cycle arrest at pre-G1 G2-M phases induced apoptosis both early late apoptotic stages. level TNF-α IL6 inhibited IL6. MD simulations studies performed over 100 ns.

Language: Английский

Citations

41
Design, synthesis and molecular docking of new fused 1H-pyrroles, pyrrolo[3,2-d]pyrimidines and pyrrolo[3,2-e][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors DOI Creative Commons
Amany Belal,

Nagwa M. Abdel Gawad,

Ahmed B. M. Mehany

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 1884 - 1902

Published: July 8, 2022

A new series of 1H-pyrrole (6a-c, 8a-c), pyrrolo[3,2-d]pyrimidines (9a-c) and pyrrolo[3,2-e][1, 4]diazepines (11a-c) were designed synthesised. These compounds to have the essential pharmacophoric features EGFR Inhibitors, they shown anticancer activities against HCT116, MCF-7 Hep3B cancer cells with IC50 values ranging from 0.009 2.195 µM. value doxorubicin is 0.008 µM, 9a 9c showed 0.011 µM respectively HCT-116 cells. Compound 8b exerted broad-spectrum activity all tested cell lines an less than 0.05 was evaluated a panel kinases. This compound potently inhibited CDK2/Cyclin A1, DYRK3 GSK3 alpha kinases 10-23% compared imatinib (1-10%). It has also arrested cycle at S phase. Its antiproliferative further augmented by molecular docking into active sites CDK2 cyclin A1.

Language: Английский

Citations

41