Angiogenic signaling pathways and anti-angiogenic therapy for cancer

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Май 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

Язык: Английский

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

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2021, Номер 37(1), С. 403 - 416

Опубликована: Дек. 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

Язык: Английский

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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

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2022, Номер 37(1), С. 1903 - 1917

Опубликована: Июль 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

Язык: Английский

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New quinoxaline-based VEGFR-2 inhibitors: design, synthesis, and antiproliferative evaluation with in silico docking, ADMET, toxicity, and DFT studies

RSC Advances, Год журнала: 2021, Номер 11(48), С. 30315 - 30328

Опубликована: Янв. 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.

Язык: Английский

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New quinoline and isatin derivatives as apoptotic VEGFR-2 inhibitors: design, synthesis, anti-proliferative activity, docking, ADMET, toxicity, and MD simulation studies

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2022, Номер 37(1), С. 2191 - 2205

Опубликована: Авг. 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.

Язык: Английский

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

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(13), С. 6912 - 6912

Опубликована: Июнь 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.

Язык: Английский

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The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1H-Indole Derivative: In Silico and In Vitro Approaches

Processes, Год журнала: 2022, Номер 10(7), С. 1391 - 1391

Опубликована: Июль 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.

Язык: Английский

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

Molecules, Год журнала: 2022, Номер 27(15), С. 5047 - 5047

Опубликована: Авг. 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

Язык: Английский

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Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2022, Номер 37(1), С. 1389 - 1403

Опубликована: Май 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.

Язык: Английский

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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

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2022, Номер 37(1), С. 1884 - 1902

Опубликована: Июль 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.

Язык: Английский

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