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

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

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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, 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

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Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 66(1), P. 777 - 792

Published: Dec. 16, 2022

Telomerase is an outstanding biological target for cancer treatment. BIBR1532 a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising inhibitors. Therefore, two novel series of pyridazine-linked cyclopenta[b]thiophene (8a-f) and tetrahydro-1-benzothiophene (9a-f) were synthesized. A quantitative real-time polymerase chain reaction was utilized investigate the inhibitory activity candidates. Notably, 8e 9e exhibited best inhibition profiles. Moreover, showed strong antitumor effects against both MCF-7 A549 cell lines. The on cycle apoptosis measured. Besides, evaluated its in vivo using solid Ehrlich carcinoma. reduction tumor weight volume greater than doxorubicin. Also, molecular docking ADME studies performed. Finally, SAR study conducted gain further insights into different potentials upon variable structural modifications.

Language: Английский

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(E)-N-(3-(1-(2-(4-(2,2,2-Trifluoroacetamido)benzoyl)hydrazono)ethyl)phenyl)nicotinamide: A Novel Pyridine Derivative for Inhibiting Vascular Endothelial Growth Factor Receptor-2: Synthesis, Computational, and Anticancer Studies

Molecules, Journal Year: 2022, Volume and Issue: 27(22), P. 7719 - 7719

Published: Nov. 9, 2022

(E)-N-(3-(1-(2-(4-(2,2,2-Trifluoroacetamido)benzoyl)hydrazono)ethyl)phenyl)nicotinamide (compound 10) was designed as an antiangiogenic VEGFR-2 inhibitor with the essential pharmacophoric structural properties to interact catalytic pocket of VEGFR-2. The derivative synthesized, and its structure confirmed through Ms, elemental, 1H, 13C spectral data. potentiality pyridine bind inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) enzyme indicated by molecular docking assessments. In addition, six dynamic (MD) experiments proved correct binding over 100 ns. Additionally, mechanics energies, combined generalized born surface area (MM-GBSA) analysis, identified precise optimum energy. To explore stability reactivity derivative, density functional theory (DFT) calculations, including electrostatic potential maps total electron density, were carried out. absorption, distribution, metabolism, excretion, toxicity (ADMET) analysis demonstrated general likeness safety. compound synthesized evaluate effects against protein, cancer, normal cells. in vitro results concordant silico results, because new displayed inhibition IC50 value 65 nM potent cytotoxic hepatic (HepG2) breast (MCF-7) cancer cell lines values 21.00 26.10 μM, respectively; additionally, it exhibited high selectivity indices (W-38) 1.55 1.25, respectively. obtained present 10 a lead for further biological investigation chemical modifications.

Language: Английский

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Discovery of new quinoline and isatine derivatives as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative, docking and MD simulation studies

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 41(21), P. 11535 - 11550

Published: Jan. 8, 2023

A new set of quinoline and isatine derivatives were synthesized as antiangiogenic VEGFR-2 inhibitors. On a biological level, the in vitro ability obtained candidates to inhibit was found be strong with IC50 values range 76.64-175.50 nM. To investigate cytotoxicity safety, all compounds tested against panel four cancer cell lines (A549, Caco2, HepG2 MDA) well two normal (Vero WI-38). Interestingly, compound 12 exhibited noticeable A549, Caco2 MDA 5.40, 0.58 0.94 µM, respectively. These results better comparable that doxorubicin (0.70, 0.82 0.90 respectively) more than three folds higher selectivity index lines. Compound 9 prevented healing cells at low concentration. Also, compound's potential induce programmed death Caco-2 proved through significant down regulating expression Bcl2, Bcl-xl Survivin addition slight upregulation TGF-β gene. The cycle analysis indicated arrested G2/M phase. molecular docking studies revealed correct binding targeted similar sorafenib. Furthermore, MD experiments validated over 100 ns, MM-PBSA confirmed precise optimum energy. Finally, ADMET showed general drug-likeness safety compounds.Communicated by Ramaswamy H. Sarma.

Language: Английский

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Recent advances in nitrogen-containing heterocyclic compounds as receptor tyrosine kinase inhibitors for the treatment of cancer: Biological activity and structural activity relationship

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 138, P. 106680 - 106680

Published: June 17, 2023

Language: Английский

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Design, semi-synthesis, anti-cancer assessment, docking, MD simulation, and DFT studies of novel theobromine-based derivatives as VEGFR-2 inhibitors and apoptosis inducers

Computational Biology and Chemistry, Journal Year: 2023, Volume and Issue: 107, P. 107953 - 107953

Published: Aug. 30, 2023

Language: Английский

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New Anticancer Theobromine Derivative Targeting EGFRWT and EGFRT790M: Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies

Molecules, Journal Year: 2022, Volume and Issue: 27(18), P. 5859 - 5859

Published: Sept. 9, 2022

Based on the pharmacophoric features of EGFR inhibitors, a new semisynthetic theobromine-derived compound was designed to interact with catalytic pocket EGFR. Molecular docking against wild (EGFRWT; PDB: 4HJO) and mutant (EGFRT790M; 3W2O) types EGFR-TK indicated that theobromine derivative had potential bind as an antiangiogenic inhibitor. The MD MM-GBSA experiments identified exact binding optimum energy dynamics. Additionally, DFT calculations studied electrostatic potential, stability, total electron density derivative. Both in silico ADMET toxicity analyses demonstrated its general likeness safety. We synthesized (compound XI) which showed IC50 value 17.23 nM for inhibition besides values 21.99 22.02 µM cytotoxicity A549 HCT-116 cell lines, respectively. Interestingly, XI expressed weak cytotoxic healthy W138 line (IC50 = 49.44 µM, 1.6 times safer than erlotinib), exhibiting high selectivity index 2.2. Compound arrested growth at G2/M stage increased incidence apoptosis.

Language: Английский

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Biological evaluation, docking studies, and in silico ADME prediction of some pyrimidine and pyridine derivatives as potential EGFR ^WT and EGFR ^T790M inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 38(1), P. 176 - 191

Published: Nov. 1, 2022

Herein, a set of pyridine and pyrimidine derivatives were assessed for their impact on the cell cycle apoptosis. Human breast cancer (MCF7), hepatocellular carcinoma (HEPG2), larynx (HEP2), lung (H460), colon cancers (HCT116 Caco2), hypopharyngeal (FADU), normal Vero lines used. Compounds 8 14 displayed outstanding effects investigated further tested antioxidant activity in MCF7, H460, FADU, HEP2, HEPG2, HCT116, Caco2, cells by measuring superoxide dismutase (SOD), malondialdehyde content (MDA), reduced glutathione (GSH), nitric oxide (NO) content. Besides, Annexin V-FITC apoptosis detection DNA index using HEPG-2 line established both compounds as well. Furthermore, EGFR kinase (Wild T790M) inhibitory activities, revealing eligible potential. Additionally, molecular docking, ADME, SAR studies carried out candidates.

Language: Английский

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An outlook of docking analysis and structure-activity relationship of pyrimidine-based analogues as EGFR inhibitors against non-small cell lung cancer (NSCLC)

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 42(18), P. 9795 - 9811

Published: Aug. 29, 2023

AbstractAlmost 80% of lung cancer diagnoses each year correspond to non-small cell (NSCLC). The percentage NSCLC with EGFR overexpression ranges from 40% 89%, squamous tumors showing the greatest rates (89%) and adenocarcinomas lowest (41%). Therefore, in therapy, blocking EGFR-driven pathway by inhibiting intracellular tyrosine kinase domain has exhibited significant improvement. In this view, several small molecules particularly pyrimidine/fused pyrimidine scaffolds were intended for molecular hybridization develop EGFR-TK inhibitors. However, associated limitation such as resistance genetic mutation along adverse effects, constrained long-term treatment effectiveness medication. recent years, derivatives uncovered potential TKIs. present review summarised research progress TKIs dazed structure-activity relationship, biological evaluation, comparative docking studies compounds. We have added analysis followed simulation study against four different PDBs strengthen already existing research. Docking unfolded that compound 14 resulted noticeable all PDB managed interact some crucial amino acid residues. From a future perspective, researchers must more selective inhibitor, can selectively target mutation. Our will support medicinal chemists direction development novel pyrimidine-based TKIs.Communicated Ramaswamy H. SarmaKeywords: TKIsdockingmutationstructural-activity relationshipcancerpyrimidine Disclosure statementThe authors co-authors confirmed they do not any personal relationships or financial competition could seemed affect current reported work.Additional informationFundingCurrent work was sponsored ICMR (No. 5/13/12/2020/NCD-III No. 5/13/79/2020/NCD-III) projects Acharya & B M Reddy college Pharmacy, Bengaluru.

Language: Английский

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