Design and green synthesis of novel quinolinone derivatives of potential anti-breast cancer activity against MCF-7 cell line targeting multi-receptor tyrosine kinases

Mokhtar, Mohamed; Alghamdi, Khadijah S; Ahmed, Nesreen S.; Bakhotmah, Dina A.; Saleh, Tamer S.

doi:10.1080/14756366.2021.1944126

Cited by 11 publications

(1 citation statement)

References 52 publications

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“…Quinoxaline is a privileged scaffold and one of the main blocks of different anticancer agents as it has been proven to be selective adenosine triphosphate (ATP) competitive as well as a bioisostere to benzimidazole, quinazolinones, isoquinolinones, phenanthridone, or phthalazinones, which are the basic scaffolds of the plurality of PARP-1 inhibitors [ 25 , 26 , 27 ]. In addition, sulfonyl and sulfonamide moieties conjugated to different heterocyclic ring systems have been reported as one of the most privileged scaffolds to inhibit the growth of various human cancer cell lines via different modes of action [ 28 , 29 ]. Cancer treatment is still a challenge due to the development of cancer cell resistance, toxicity, and the lack of selectivity of most commercialized anticancer medications.…”

Section: Introductionmentioning

confidence: 99%

New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies

et al. 2022

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Herein, 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was used as a bio-isosteric scaffold to the phthalazinone motif of the standard drug Olaparib to design and synthesize new derivatives of potential PARP-1 inhibitory activity using the 6-sulfonohydrazide analog 3 as the key intermediate. Although the new compounds represented the PARP-1 suppression impact of IC50 values in the nanomolar range, compounds 8a, 5 were the most promising suppressors, producing IC50 values of 2.31 and 3.05 nM compared to Olaparib with IC50 of 4.40 nM. Compounds 4, 10b, and 11b showed a mild decrease in the potency of the IC50 range of 6.35–8.73 nM. Furthermore, compounds 4, 5, 8a, 10b, and 11b were evaluated as in vitro antiproliferative agents against the mutant BRCA1 (MDA-MB-436, breast cancer) compared to Olaparib as a positive control. Compound 5 exhibited the most significant potency of IC50; 2.57 µM, whereas the IC50 value of Olaparib was 8.90 µM. In addition, the examined derivatives displayed a promising safety profile against the normal WI-38 cell line. Cell cycle, apoptosis, and autophagy analyses were carried out in the MDA-MB-436 cell line for compound 5, which exhibited cell growth arrest at the G2/M phase, in addition to induction of programmed apoptosis and an increase in the autophagic process. Molecular docking of the compounds 4, 5, 8a, 10b, and 11b into the active site of PARP-1 was carried out to determine their modes of interaction. In addition, an in silico ADMET study was performed. The results evidenced that compound 5 could serve as a new framework for discovering new potent anticancer agents targeting the PARP-1 enzyme.

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Section: Introductionmentioning

confidence: 99%

New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies

et al. 2022

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Identification of novel sulfathiazole‐triazolo‐chalcone hybrids as VEGFR‐2/EGFR dual inhibitors with antiangiogenic activity and apoptotic induction

Zeidan,

Othman,

Goda

et al. 2023

Archiv der Pharmazie

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Certain sulfathiazole‐triazolo chalcone hybrids were identified as anticancer agents with dual vascular endothelial growth factor receptor‐2 (VEGFR‐2)/epidermal growth factor receptor (EGFR) kinase inhibitory effect. All of the compounds were evaluated for their cytotoxic activity against the MCF‐7 and HepG‐2 tumor cell lines. Compounds 11g, 11h, and 11j exhibited the most potent antiproliferative activity against both cancer cell lines, with good safety toward WI‐38 normal cells. Thus, they were further assessed for VEGFR‐2 inhibitory activity. They have suppressed VEGFR‐2 enzyme at IC50 of 0.316, 0.076, and 0.189 µM, respectively in comparison to sorafenib (IC50 = 0.035 µM). EGFR enzyme inhibition was further screened for the most potent inhibitors, 11h and 11j, where they displayed enhanced potency with IC50 of 0.085 and 0.108 µM, respectively, compared to erlotinib (IC50 = 0.037 µM). Compounds 11h and 11j were additionally investigated for inhibition of comparable kinases, PDGFR‐β and B‐Raf, where results assessed adequate selectivity of both compounds toward the VEGFR‐2 and EGFR kinases. Furthermore, the wound healing assay of compound 11h manifested a percent wound closure of 65.18% in MCF‐7 cells compared to doxorubicin (58.51%) and untreated cells (97.77%), proving its antiangiogenic activity. The cell cycle assay of MCF‐7 cells treated with 11h demonstrated cell cycle arrest at the S phase. Moreover, compound 11h induced apoptosis with a 44‐fold increase compared to that induced in the control MCF‐7 cells. Molecular docking results of compounds 11h and 11j established their efficacies, and in silico studies showed convenient safety profiles with drug‐likeness properties.

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Imidazo[1,2,4]triazolone and fused imidazo[1,2,4]triazolone derivatives: Synthesis, in vitro anticancer screening, CDK2 inhibitory activity, and molecular modeling studies

Rabeeb

Deeb

Sarg

et al. 2022

Journal of Heterocyclic Chem

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In continuation of our program for synthesizing novel imidazotriazole scaffolds, we report herein the synthesis of new fifteen substituted and fused imidazotriazole derivatives via different addition and cyclocondensation pathways. Thirteen compounds have been tested for their antiproliferative activity against 60 NCI cell lines. Compounds 3, 15 and 17 were the most active among the synthesized series. Imidazo[2,1-c][1,2,4]triazolone derivative 3 showed high activity against leukemia K-562 (51.00%), RPMI-8226 (68.36%) and breast cancer MCF-7 (56.76%) cell lines. While compound 15 exhibited high potency against colon cancer HCT-15 (59.33%), CNS cancer SNB-75 (57.06%) and renal cancer UO-31 (50.5%) cell lines. Bis[1,2,4]triazolopurin-7-one derivative 17 showed strong activity against CNS cancer SNB-75 cell line (54.32%). Compounds 3, 15 and 17 were evaluated through molecular modeling and docking techniques to give us a closer look on their binding mode with CDK2. The in vitro inhibitory activity against CDK2 was also performed for compounds 3 and 17. Compound 3 was subjected to further investigations by studying its effect on cell cycle progression and cell apoptosis in MCF-7 cell line. It caused apoptosis, necrosis and induced cell cycle arrest at G2/M phase in MCF-7 cell.

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Design and green synthesis of novel quinolinone derivatives of potential anti-breast cancer activity against MCF-7 cell line targeting multi-receptor tyrosine kinases

Cited by 11 publications

References 52 publications

New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies

New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies

Identification of novel sulfathiazole‐triazolo‐chalcone hybrids as VEGFR‐2/EGFR dual inhibitors with antiangiogenic activity and apoptotic induction

Imidazo[1,2,4]triazolone and fused imidazo[1,2,4]triazolone derivatives: Synthesis, in vitro anticancer screening, CDK2 inhibitory activity, and molecular modeling studies

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