Synthesis, anticancer activity and molecular docking of new triazolo[4,5-<i>d</i>]pyrimidines based thienopyrimidine system and their derived <i>N</i>-glycosides and thioglycosides

Khattab, Reham R.; Hassan, Allam A.; Osman, Dalia Ahmed A.; Abdel‐Megeid, Farouk M. E.; Awad, Hanem M.; Nossier, Eman S.; El‐Sayed, Wael A.

doi:10.1080/15257770.2021.1975297

Cited by 16 publications

(12 citation statements)

References 36 publications

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“… 60 These types of cancer cell lines have a high expression of EGFR, VEGFR and BRAF. 10,11,17,18,26 In addition, the cytotoxic effect of the new compounds was also evaluated against the normal lung fibroblast (WI38) to demonstrate their safety profiles. The commercially available doxorubicin was utilized as a standard drug.…”

Section: Resultsmentioning

confidence: 99%

“…The overexpression of EGFR in a variety of human cancers, including head, neck, breast, lung, colorectal, prostate, renal, pancreas, ovary, and brain cancers results in poor treatment outcomes due to resistance to hormone therapy, cytotoxic drugs, and radiotherapy. 10,11 As a result, international recommendations advocate anti-EGFR medicines as the first-line treatment in patients with advanced EGFR mutations, due to their higher efficacy and safety compared to standard chemotherapy. 9,12,13 …”

Section: Introductionmentioning

confidence: 99%

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Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors

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“…Computational studies represented that the ATP active pocket of EGFR-TK possesses mainly five regions, as follows: (1) an adenine binding pocket bearing the key amino acid residues that can interact with the adenine ring via hydrogen bond formation, (2) a sugar zone (hydrophilic ribose pocket), (3) hydrophobic zone I (this area is not used by ATP but displays a pivotal role in the inhibitor selectivity), (4) hydrophobic region II (this area is also not used by ATP and can be used to determine the inhibitor specificity), and (5) a phosphate binding area that is important for improving the characteristics of inhibitor pharmacokinetics , (Figure ).…”

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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“…The epidermal growth factor receptor (EGFR) tyrosine kinase controls many bioactivities, such as regulation of the cell cycle, adhesion and cell motility [ 8 ]. Therefore, over-expression or mutations of EGFR stimulate cell angiogenesis, proliferation, metastasis and anti-apoptosis affording different epidermal carcinomas, especially colon, breast and bladder cancers [ 9 , 10 , 11 , 12 ]. Vascular endothelial growth factor (VEGF) tyrosine kinase receptor is a family of the most crucial and specific signaling proteins involved in both pathological and physiological angiogenesis [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

New 1,2,3-Triazole-Coumarin-Glycoside Hybrids and Their 1,2,4-Triazolyl Thioglycoside Analogs Targeting Mitochondria Apoptotic Pathway: Synthesis, Anticancer Activity and Docking Simulation

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Toxicity and resistance to newly synthesized anticancer drugs represent a challenging phenomenon of intensified concern arising from variation in drug targets and consequently the prevalence of the latter concern requires further research. The current research reports the design, synthesis, and anticancer activity of new 1,2,3-triazole-coumarin-glycosyl hybrids and their 1,2,4-triazole thioglycosides as well as acyclic analogs. The cytotoxic activity of the synthesized products was studied against a panel of human cancer cell lines. Compounds 8, 10, 16 and 21 resulted in higher activities against different human cancer cells. The impact of the hybrid derivative 10 upon different apoptotic protein markers, including cytochrome c, Bcl-2, Bax, and caspase-7 along with its effect on the cell cycle was investigated. It revealed a mitochondria-apoptotic effect on MCF-7 cells and had the ability to upregulate pro-apoptotic Bax protein and downregulate anti-apoptotic Bcl-2 protein and thus implies the apoptotic fate of the cells. Furthermore, the inhibitory activities against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases for 8, 10 and 21 were studied to detect the mechanism of their high potency. The coumarin-triazole-glycosyl hybrids 8 and 10 illustrated excellent broad inhibitory activity (IC50= 0.22 ± 0.01, 0.93 ± 0.42 and 0.24 ± 0.20 μM, respectively, for compound 8), (IC50 = 0.12 ± 0.50, 0.79 ± 0.14 and 0.15± 0. 60 μM, respectively, for compound 10), in comparison with the reference drugs, erlotinib, sorafenib and roscovitine (IC50 = 0.18 ± 0.05, 1.58 ± 0.11 and 0.46 ± 0.30 μM, respectively). In addition, the docking study was simulated to afford better rationalization and put insight into the binding affinity between the promising derivatives and their targeted enzymes and that might be used as an optimum lead for further modification in the anticancer field.

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Synthesis, anticancer activity and molecular docking of new triazolo[4,5-d]pyrimidines based thienopyrimidine system and their derived N-glycosides and thioglycosides

Cited by 16 publications

References 36 publications

Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors

Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors

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

New 1,2,3-Triazole-Coumarin-Glycoside Hybrids and Their 1,2,4-Triazolyl Thioglycoside Analogs Targeting Mitochondria Apoptotic Pathway: Synthesis, Anticancer Activity and Docking Simulation

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Synthesis, anticancer activity and molecular docking of new triazolo[4,5-d]pyrimidines based thienopyrimidine system and their derived N-glycosides and thioglycosides

Cited by 16 publications

References 36 publications

Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors

Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors

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

New 1,2,3-Triazole-Coumarin-Glycoside Hybrids and Their 1,2,4-Triazolyl Thioglycoside Analogs Targeting Mitochondria Apoptotic Pathway: Synthesis, Anticancer Activity and Docking Simulation

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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