New pyrimidine and pyrazole-based compounds as potential EGFR inhibitors: Synthesis, anticancer, antimicrobial evaluation and computational studies

Othman, Ismail M.M.; Alamshany, Zahra M.; Tashkandi, Nada Y.; Gad‐Elkareem, Mohamed A. M.; Anwar, Manal M.; Nossier, Eman S.

doi:10.1016/j.bioorg.2021.105078

Cited by 64 publications

(31 citation statements)

References 52 publications

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“…It was reported that these molecules were cytotoxic when analyzed using the MCF-7 cell line (0.01 ± 0.003 µM for 323 , 0.02 ± 0.001 µM for 324 , 0.04 ± 0.04 µM for 325 , 0.08 ± 0.02 µM for 326, and 0.42 ± 0.2 µM for erlotinib, which was used as standard). The EGFR kinase inhibitory activity revealed that the molecules have displayed very little activity in inhibiting the EGFR WT ( Othman et al, 2021 ).…”

Section: Fused Pyrimidine Derivativesmentioning

confidence: 99%

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship

et al. 2022

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Epidermal growth factor receptor (EGFR) belongs to the family of tyrosine kinase that is activated when a specific ligand binds to it. The EGFR plays a vital role in the cellular proliferation process, differentiation, and apoptosis. In the case of cancer, EGFR undergoes uncontrolled auto-phosphorylation that results in increased cellular proliferation and decreased apoptosis, causing cancer promotion. From the literature, it shows that pyrimidine is one of the most commonly studied heterocycles for its antiproliferative activity against EGFR inhibition. The authors have collated some interesting results in the heterocycle-fused pyrimidines that have been studied using different cell lines (sensitive and mutational) and in animal models to determine their activity and potency. It is quite clear that the fused systems are highly effective in inhibiting EGFR activity in cancer cells. Therefore, the structure–activity relationship (SAR) comes into play in determining the nature of the heterocycle and the substituents that are responsible for the increased activity and toxicity. Understanding the SAR of heterocycle-fused pyrimidines will help in getting a better overview of the molecules concerning their activity and potency profile as future EGFR inhibitors.

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Section: Fused Pyrimidine Derivativesmentioning

confidence: 99%

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship

et al. 2022

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“… 7 , 8 EGFR is one of the main tumor markers in many cancer types (such as colon, lung, liver, cervical, ovarian, breast, prostate, and bladder cancers), where its signaling in tumors, as opposed to normal cells, becomes dysregulated, resulting in EGFR overexpression and/or obtaining a gain-of-function mutation. 9 − 13 This act is considered the main cause of tumor cell proliferation, invading the surrounding tissues and resulting in an increased angiogenesis. 14 Accordingly, interrupting EGFR communicating signals is considered to be one of the prime targets to invade tumors caused by its mis-regulation.…”

Section: Introductionmentioning

confidence: 99%

“… 14 Accordingly, interrupting EGFR communicating signals is considered to be one of the prime targets to invade tumors caused by its mis-regulation. 9 − 14 Targeted drugs inhibiting EGFR can selectively attack the cancer cells rather than normal ones, thus producing a good safety profile and less harm to the body with more patient comfortability. 15 Multiple EGFR suppressors have been developed and classified into different generations.…”

Section: Introductionmentioning

confidence: 99%

New Benzimidazole-, 1,2,4-Triazole-, and 1,3,5-Triazine-Based Derivatives as Potential EGFR^WT and EGFR^T790M Inhibitors: Microwave-Assisted Synthesis, Anticancer Evaluation, and Molecular Docking Study

et al. 2022

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A new series of benzimidazole, 1,2,4-triazole, and 1,3,5-triazine derivatives were designed and synthesized using a microwave irradiation synthetic approach utilizing 2-phenylacetyl isothiocyanate (1) as a key starting material. All the new analogues were evaluated as anticancer agents against a panel of cancer cell lines utilizing doxorubicin as a standard drug. Most of the tested derivatives exhibited selective cytotoxic activity against MCF-7 and A-549 cancer cell lines. Furthermore, the new target compounds 5 , 6 , and 7 as the most potent antiproliferative agents have been assessed as in vitro EGFR WT and EGFR T790M inhibitors compared to the reference drugs erlotinib and AZD9291. They represented more potent suppression activity against the mutated EGFR T790M than the wild-type EGFR WT . Moreover, the compounds 5 , 6 , and 7 down-regulated the oncogenic parameter p53 ubiquitination. A docking simulation of compound 6b was carried out to correlate its molecular structure with its significant EGFR inhibition potency and its possible binding interactions within the active site of EGFR WT and the mutant EGFR T790M .

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“…It is overexpressed in a multiplicity of human cancers, including breast, colorectal, lung, prostate, ovary and pancreatic cancers [ 6 , 7 ]. Poor treatment outcomes as a result of resistance to radiotherapy, hormone therapy, and cytotoxic drugs presented an opportunity for anti-EGFR drug recommendations due to their higher safety and efficacy compared to standard chemotherapy [ 5 , 8 , 9 ]. Moreover, vascular endothelial growth factor receptor-2 (VEGFR-2) has a crucial role in the induction of angiogenesis [ 10 , 11 , 12 ], which is correlated with tumour growth, invasion and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Novel 1,2,3-Triazole-Coumarin Hybrid Glycosides and Their Tetrazolyl Analogues: Design, Anticancer Evaluation and Molecular Docking Targeting EGFR, VEGFR-2 and CDK-2

et al. 2022

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This study represents the design and synthesis of a new set of triazole-coumarin-glycosyl hybrids and their tetrazole hybrid analogues possessing various sugar moieties and modified analogues. All the newly synthesized derivatives were screened for their cytotoxic activities against a panel of human cancer cell lines. The coumarin derivatives 10, 13 and 15 derivatives revealed potent cytotoxic activities against Paca-2, Mel-501, PC-3 and A-375 cancer cell lines. These promising analogues were further examined for their inhibitory assessment against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases. The coumarin-tetrazole 10 displayed broad superior inhibitory activity against all screened enzymes compared with the reference drugs, erlotinib, sorafenib and roscovitine, respectively. The impact of coumarin-tetrazole 10 upon cell cycle and apoptosis induction was determined to detect its mechanism of action. Additionally, it upregulated the levels of casp-3, casp-7 and cytochrome-c proteins and downregulated the PD-1 level. Finally, molecular docking study was simulated to afford better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes, which could be used as an optimum lead for further modification in the anticancer field.

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New pyrimidine and pyrazole-based compounds as potential EGFR inhibitors: Synthesis, anticancer, antimicrobial evaluation and computational studies

Cited by 64 publications

References 52 publications

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship

New Benzimidazole-, 1,2,4-Triazole-, and 1,3,5-Triazine-Based Derivatives as Potential EGFR^WT and EGFR^T790M Inhibitors: Microwave-Assisted Synthesis, Anticancer Evaluation, and Molecular Docking Study

Novel 1,2,3-Triazole-Coumarin Hybrid Glycosides and Their Tetrazolyl Analogues: Design, Anticancer Evaluation and Molecular Docking Targeting EGFR, VEGFR-2 and CDK-2

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New pyrimidine and pyrazole-based compounds as potential EGFR inhibitors: Synthesis, anticancer, antimicrobial evaluation and computational studies

Cited by 64 publications

References 52 publications

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship

New Benzimidazole-, 1,2,4-Triazole-, and 1,3,5-Triazine-Based Derivatives as Potential EGFRWT and EGFRT790M Inhibitors: Microwave-Assisted Synthesis, Anticancer Evaluation, and Molecular Docking Study

Novel 1,2,3-Triazole-Coumarin Hybrid Glycosides and Their Tetrazolyl Analogues: Design, Anticancer Evaluation and Molecular Docking Targeting EGFR, VEGFR-2 and CDK-2

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New Benzimidazole-, 1,2,4-Triazole-, and 1,3,5-Triazine-Based Derivatives as Potential EGFR^WT and EGFR^T790M Inhibitors: Microwave-Assisted Synthesis, Anticancer Evaluation, and Molecular Docking Study