Quinoline–hydrazone hybrids as dual mutant EGFR inhibitors with promising metallic nanoparticle loading: rationalized design, synthesis, biological investigation and computational studies

Elrayess, Ranza; Darwish, Khaled M.; Nafie, Mohamed S.; El-Sayyad, Gharieb S.; Said, Mohamed M.; Yassen, Asmaa S. A.

doi:10.1039/d2nj02962f

Cited by 8 publications

(8 citation statements)

References 112 publications

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“…Atomic coordinates of the biological targets ECT2 and LARG were acquired from the respective deposited Protein Data Bank (PDB) files 6L30 [ 40 ] and 1X86 [ 41 ] and then prepared within AutoDock Vina by removing ion/solvent/water, computing Gasteiger partial charges, and introducing polar/non-polar hydrogen atoms being missed from the crystallized proteins [ 42 ]. Both N -terminal BRCT units were removed, keeping only the C-terminal catalytic Dbl oncoprotein and pleckstrin homology (DH-PH) domains.…”

Section: Methodsmentioning

confidence: 99%

Integration of Chemoinformatics and Multi-Omics Analysis Defines ECT2 as a Potential Target for Cancer Drug Therapy

Soltan

Eldeen

Sajer

et al. 2023

Biology

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Epithelial cell transforming 2 (ECT2) is a potential oncogene and a number of recent studies have correlated it with the progression of several human cancers. Despite this elevated attention for ECT2 in oncology-related reports, there is no collective study to combine and integrate the expression and oncogenic behavior of ECT2 in a panel of human cancers. The current study started with a differential expression analysis of ECT2 in cancerous versus normal tissue. Following that, the study asked for the correlation between ECT2 upregulation and tumor stage, grade, and metastasis, along with its effect on patient survival. Moreover, the methylation and phosphorylation status of ECT2 in tumor versus normal tissue was assessed, in addition to the investigation of the ECT2 effect on the immune cell infiltration in the tumor microenvironment. The current study revealed that ECT2 was upregulated as mRNA and protein levels in a list of human tumors, a feature that allowed for the increased filtration of myeloid-derived suppressor cells (MDSC) and decreased the level of natural killer T (NKT) cells, which ultimately led to a poor prognosis survival. Lastly, we screened for several drugs that could inhibit ECT2 and act as antitumor agents. Collectively, this study nominated ECT2 as a prognostic and immunological biomarker, with reported inhibitors that represent potential antitumor drugs.

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Section: Methodsmentioning

confidence: 99%

Integration of Chemoinformatics and Multi-Omics Analysis Defines ECT2 as a Potential Target for Cancer Drug Therapy

Soltan

Eldeen

Sajer

et al. 2023

Biology

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“…MTT assay (IC 50 , μM) was performed in accordance with previously reported method [26] . See Appendix A.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, the N ‐acyl Schiff base VI showed antiproliferative activity against MCF‐7 breast cancer cell line with IC 50 value 10.98 μM [25] . Furthermore, the quinoline‐Schiff base hybrids demonstrated exceptionally mutant EGFR inhibition activity with IC 50 values 22.1 to 36.4 nM inducing cell cycle arrest of MCF‐7 breast cancerous cells within the S phase causing cellular apoptosis [26] …”

Section: Introductionmentioning

confidence: 99%

“…[25] Furthermore, the quinoline-Schiff base hybrids demonstrated exceptionally mutant EGFR inhibition activity with IC 50 values 22.1 to 36.4 nM inducing cell cycle arrest of MCF-7 breast cancerous cells within the S phase causing cellular apoptosis. [26] Inspired by all these findings, the aim of this work is to prepare new anticancer candidates via linking enamide motif carrying both trimethoxyphenyl (TMP) and 4-fluorophenyl rings with different Schiff bases using the hydrazide liker as a possible tubulin inhibitor with potent antiproliferative activity (Figure 2). The in vitro cytotoxic activity of the new enamide-Schiff base hybrids was evaluated utilizing MTT assay method using MCF-7 breast cancer cell line.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Characterization and Biological Evaluation of New Enamide Fluorinated‐Schiff Base Derivatives as Potential Cytotoxic and Apoptosis‐Inducing Agents

Abd El‐Lateef,

Toson,

Abu Almaaty

et al. 2023

ChemistrySelect

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In search for new anticancer candidates, a new series of enamide fluorinated‐Schiff base derivatives were synthesized and confirmed by spectroscopic techniques as well as elemental microanalyses. The newly prepared compounds were evaluated for their cytotoxic activity on MCF‐7 breast adenocarcinoma cell line. The benzaldehyde Schiff base and furfural Schiff base derivatives (IC50=3.67±0.15 and 2.06±0.08 μM, respectively) were found to be the most potent molecules of all the tested derivatives against the MCF‐7 cancer cells. Additionally, the furfural Schiff base compound was more potent than colchicine by 1.74‐fold, while benzaldehyde Schiff base compound was nearly equipotent with colchicine as standard drug. In addition to tubulin inhibition activity, enamide‐furfural Schiff base molecule caused cell cycle arrest in MCF‐7 cells at the G2/M phase (2.62‐fold more than control MCF‐7) and induced apoptotic death (48.97‐fold compared to untreated MCF‐7 control) as indicated by FACS analysis. Furthermore, apoptotic studies conducted by enamide‐furfural Schiff base derivative were accomplished by downregulation of mitochondrial membrane potential by 1.56‐fold relative to control untreated cells.

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“…[19] Hydrazone derivatives represent a unique class of kinase inhibitors as well. [20,21] A featured series of hydrazones were proved to have significant inhibitory activity against HER-2; among which compound 7 was the most potent. [22] Moreover, sulfonyl hydrazone substituted derivatives 8 and 9 are phosphoinositide 3-kinase (PI3K) p110α inhibitor (Figure 2).…”

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confidence: 99%

Exploration of antiproliferative potential of modified triazole–benzohydrazone scaffold: Multitarget approach

Ali,

Khalaf,

Bhongade

et al. 2023

Archiv der Pharmazie

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A novel series of triazole–benzohydrazone hybrids was efficiently designed and synthesized as antiproliferative agents, targeting different kinases. All compounds were screened via the National Cancer Institute (NCI) against 60 cancer cell lines, where compounds 16, 17, and 18 exhibited growth inhibition percent (GI%) of various leukemia subpanels with values of 70.33%, 64.13%, and 76.03%, respectively. Compound 18 showed broad‐spectrum antiproliferative efficacy toward most cancer cells, with outstanding potency regarding melanoma (MALME‐3M GI% = 101.82%) and breast cancer cell lines (MCF7 GI% = 85.87%), while proving safe toward the WI‐38 normal cell line, compared to doxorubicin. Multikinase investigation including vascular endothelial growth factor receptor 2 (VEGFR‐2), mesenchymal epithelial transition factor (c‐Met), proto‐oncogene B‐Raf, mitogen‐activated protein kinase kinase, extracellular signal‐regulated kinase, and phosphoinositide 3‐kinase was accomplished to reveal its plausible mechanism of action, giving the ultimate potency against both VEGFR‐2 and c‐Met with IC50 values of 0.055 and 0.042 μM, respectively, while displaying moderate to good inhibition concerning the remaining kinases. DNA binding capability was excluded using the methyl green colorimetric assay. Further, it exhibited both early and late apoptotic induction by about 16‐ and 9.4‐fold over the control, respectively, triggering cell cycle arrest in the G2/M phase. Physicochemical properties and bioavailability radar plot inferred drug‐likeness characteristics for compound 18. The molecular docking study assessed the binding pattern with the active sites of c‐Met and VEGFR‐2.

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Quinoline–hydrazone hybrids as dual mutant EGFR inhibitors with promising metallic nanoparticle loading: rationalized design, synthesis, biological investigation and computational studies

Abstract: A novel quinoline–hydrazone hybrid induced apoptosis in MCF-7 cells through dual mutant EGFR inhibition with promising metallic nanoparticle loading.

Cited by 8 publications

References 112 publications

Integration of Chemoinformatics and Multi-Omics Analysis Defines ECT2 as a Potential Target for Cancer Drug Therapy

Integration of Chemoinformatics and Multi-Omics Analysis Defines ECT2 as a Potential Target for Cancer Drug Therapy

Synthesis, Characterization and Biological Evaluation of New Enamide Fluorinated‐Schiff Base Derivatives as Potential Cytotoxic and Apoptosis‐Inducing Agents

Exploration of antiproliferative potential of modified triazole–benzohydrazone scaffold: Multitarget approach

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