Discovery of novel thienoquinoline-2-carboxamide chalcone derivatives as antiproliferative EGFR tyrosine kinase inhibitors

Abdelbaset, Mahmoud S.; Abdel‐Aziz, Mohamed; Ramadan, Mohamed; Abdelrahman, Mostafa H.; Bukhari, Syed Nasir Abbas; Ali, Taha F. S.; Abuo‐Rahma, Gamal El‐Din A.

doi:10.1016/j.bmc.2019.02.012

Cited by 44 publications

(19 citation statements)

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“…Abdelbaset et al, for example, designed several thieno[2,3- b ]quinoline-2-carboxamide-chalcone derivatives, as molecule 54 ( Figure 26 a) that showed significant antiproliferative effects against tested cancer cell lines (IC 50 values in the range 0.9–1.2 μM) and an EGFR IC 50 = 0.5 μM. Molecular docking studies showed that the thienoquinoline moiety occupied the ATP-binding site of the receptor, whereas chalcone moiety was located in an allosteric pocket of the enzyme ( Figure 26 b) [ 124 ].…”

Section: Quinolines As Inhibitors Of Carcinogenic Pathwaysmentioning

confidence: 99%

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Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

2020

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The quinoline ring system has long been known as a versatile nucleus in the design and synthesis of biologically active compounds. Currently, more than one hundred quinoline compounds have been approved in therapy as antimicrobial, local anaesthetic, antipsychotic, and anticancer drugs. In drug discovery, indeed, over the last few years, an increase in the publication of papers and patents about quinoline derivatives possessing antiproliferative properties has been observed. This trend can be justified by the versatility and accessibility of the quinoline scaffold, from which new derivatives can be easily designed and synthesized. Within the numerous quinoline small molecules developed as antiproliferative drugs, this review is focused on compounds effective on c-Met, VEGF (vascular endothelial growth factor), and EGF (epidermal growth factor) receptors, pivotal targets for the activation of important carcinogenic pathways (Ras/Raf/MEK and PI3K/AkT/mTOR). These signalling cascades are closely connected and regulate the survival processes in the cell, such as proliferation, apoptosis, differentiation, and angiogenesis. The antiproliferative biological data of remarkable quinoline compounds have been analysed, confirming the pivotal importance of this ring system in the efficacy of several approved drugs. Furthermore, in view of an SAR (structure-activity relationship) study, the most recurrent ligand–protein interactions of the reviewed molecules are summarized.

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Section: Quinolines As Inhibitors Of Carcinogenic Pathwaysmentioning

confidence: 99%

“… ( a ) Thieno[2,3- b ]quinoline-2-carboxamide-chalcone derivative 54 ; ( b ) orientation and interactions of 54 within the EGFR active site [ 124 ]. …”

Section: Figurementioning

confidence: 99%

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

2020

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“…The structure preparation module in MOE 2019.01 (Chemical Computing Group, Montreal, QC, Canada) was applied in the preparation of the protein structures. 58 All water molecules were removed from the structure. For both COX isoforms, the co-crystallized ligand was defined as the A B center of the binding site.…”

Section: Molecular Docking Studymentioning

confidence: 99%

<p>Anti-Inflammatory Potential of Green Synthesized Silver Nanoparticles of the Soft Coral <em>Nephthea</em> Sp. Supported by Metabolomics Analysis and Docking Studies</p>

Abdelhafez

Ali

Fahim

et al. 2020

IJN

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Background: Soft corals have been endorsed as a plentiful source of bioactive compounds with promising anti-inflammatory activities; therefore, exploring their potential as source of anti-inflammatory metabolites has stimulated a growing research interest. Purpose: To investigate the anti-inflammatory potential of the soft coral, Nephthea sp., in its bulk and silver nanostructure. Metabolomics analysis of Nephthea sp., followed by molecular docking studies, was also conducted in order to explore and predict the secondary metabolites that might provide its inhibitory actions on inflammation. Materials and Methods: The petroleum ether and ethyl acetate fractions were used to synthesize silver nanoparticles. The prepared silver nanoparticles were characterized through UV-vis spectrophotometric, transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR) analyses. Testing for the anti-inflammatory activity was performed against COX-1 and COX-2. Furthermore, liquid chromatography-mass spectrometry (LC-MS) based metabolomics analysis and molecular docking were also applied. Results: A variety of secondary metabolites were identified, among them, sesquiterpenes were found to prevail. The petroleum ether and acetone fractions of Nephthea sp. showed the highest COX-2 inhibitory activities, possibly attributable to their substantial contents of terpenoids. Additionally, the green synthesized silver nanoparticles of both the petroleum ether and ethyl acetate fractions of Nephthea sp. demonstrated higher anti-COX-2 properties. Conclusion: The obtained results showed the effectiveness of non-targeted metabolomics technique in metabolic profiling of Nephthea sp., helping the search for new bioactive metabolites in future chemical studies on this soft coral. The interesting anti-inflammatory potential of the tested extracts and their nanoparticles could also be relevant to the development of new, effective anti-inflammatory agents.

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“…Therefore, it was clear that the large molecular size of compound 2e allows it to selectively bind to the inactive conformation of EGFR but not to the active configuration. Subsequently, compound 2e was docked in the inactive conformation of EGFR (PDB code: 4HJO) to elucidate the structural mechanism of EGFR inhibition by this new class of compounds [56]. It can be considered that compound 2e is an ATP-competitive EGFR inhibitor like erlotinib, although its binding affinity is lower than that of erlotinib [57].…”

Section: Molecular Dockingmentioning

confidence: 99%

“…The co-crystalized X-ray structure of erlotinib binds to the inactive conformation of the EGFR tyrosine kinase domain (PDB code: 4HJO) was used in the present study [56]. Moreover, the crystal structures of COX-1 protein (PDB code: 3KK6), where COX-1 was co-crystallized with celecoxib [69], and COX-2 protein (PDB code: 3LN1), where COX-2 co-crystallized with celecoxib [70], were retrieved from the Protein Data Bank.…”

Section: In Silico Studiesmentioning

confidence: 99%

In Vitro and In Silico Evaluation of Anticancer Activity of New Indole-Based 1,3,4-Oxadiazoles as EGFR and COX-2 Inhibitors

et al. 2020

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Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are crucial targetable enzymes in cancer management. Therefore, herein, new 2-[(5-((1H-indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)thio]-N-(thiazol/benzothiazol-2-yl)acetamides (2a–i) were designed and synthesized as EGFR and COX-2 inhibitors. The cytotoxic effects of compounds 2a–i on HCT116 human colorectal carcinoma, A549 human lung adenocarcinoma, and A375 human melanoma cell lines were determined using MTT assay. 2-[(5-((1H-Indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)thio]-N-(6-ethoxybenzothiazol-2-yl)acetamide (2e) exhibited the most significant anticancer activity against HCT116, A549, and A375 cell lines with IC50 values of 6.43 ± 0.72 μM, 9.62 ± 1.14 μM, and 8.07 ± 1.36 μM, respectively, when compared with erlotinib (IC50 = 17.86 ± 3.22 μM, 19.41 ± 2.38 μM, and 23.81 ± 4.17 μM, respectively). Further mechanistic assays demonstrated that compound 2e enhanced apoptosis (28.35%) in HCT116 cells more significantly than erlotinib (7.42%) and caused notable EGFR inhibition with an IC50 value of 2.80 ± 0.52 μM when compared with erlotinib (IC50 = 0.04 ± 0.01 μM). However, compound 2e did not cause any significant COX-2 inhibition, indicating that this compound showed COX-independent anticancer activity. The molecular docking study of compound 2e emphasized that the benzothiazole ring of this compound occupied the allosteric pocket in the EGFR active site. In conclusion, compound 2e is a promising EGFR inhibitor that warrants further clinical investigations.

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Discovery of novel thienoquinoline-2-carboxamide chalcone derivatives as antiproliferative EGFR tyrosine kinase inhibitors

Cited by 44 publications

References 30 publications

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

<p>Anti-Inflammatory Potential of Green Synthesized Silver Nanoparticles of the Soft Coral <em>Nephthea</em> Sp. Supported by Metabolomics Analysis and Docking Studies</p>

In Vitro and In Silico Evaluation of Anticancer Activity of New Indole-Based 1,3,4-Oxadiazoles as EGFR and COX-2 Inhibitors

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