Design, synthesis and antitumor activity of novel pyrazolo[3,4-d]pyrimidine derivatives as EGFR-TK inhibitors

Abdelgawad, Mohamed A.; Bakr, Rania B.; Alkhoja, Olla A.; Mohamed, Wafaa R.

doi:10.1016/j.bioorg.2016.03.011

Cited by 70 publications

(34 citation statements)

References 30 publications

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“…Targets of 5a, 5e, 5g, and 5h 2.3.1. In Silico Molecular Docking of 5a, 5e, 5g, and 5h as Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors EGFR is the first member of the Her receptor family which plays a conspicuous role in cellular signaling activities, including cell proliferation, growth, adhesion, differentiation, metabolism, motility, and death [49][50][51]. Therefore, EGFR has been regarded as a valuable anticancer target in medicinal chemistry.…”

Section: Identification Of Potential Anticancer Drugmentioning

confidence: 99%

Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones

Horchani

Sala

Caso

et al. 2021

IJMS

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Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In the search for therapeutic alternatives to treat the cancer disease, a series of hybrid pyrazolo[3 ,4-d]pyrimidin-4(5H)-ones tethered with hydrazide-hydrazones, 5a–h, was synthesized from condensation reaction of pyrazolopyrimidinone-hydrazide 4 with a series of arylaldehydes in ethanol, in acid catalysis. In vitro assessment of antiproliferative effects against MCF-7 breast cancer cells, unveiled that 5a, 5e, 5g, and 5h were the most effective compounds of the series and exerted their cytotoxic activity through apoptosis induction and G0/G1 phase cell-cycle arrest. To explore their mechanism at a molecular level, 5a, 5e, 5g, and 5h were evaluated for their binding interactions with two well-known anticancer targets, namely the epidermal growth factor receptor (EGFR) and the G-quadruplex DNA structures. Molecular docking simulations highlighted high binding affinity of 5a, 5e, 5g, and 5h towards EGFR. Circular dichroism (CD) experiments suggested 5a as a stabilizer agent of the G-quadruplex from the Kirsten ras (KRAS) oncogene promoter. In the light of these findings, we propose the pyrazolo-pyrimidinone scaffold bearing a hydrazide-hydrazone moiety as a lead skeleton for designing novel anticancer compounds.

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Section: Identification Of Potential Anticancer Drugmentioning

confidence: 99%

Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones

Horchani

Sala

Caso

et al. 2021

IJMS

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“…The biological study of these derivatives demonstrated that derivative (B) exhibited the highest inflammatory inhibition (40.09%) at dose 100 mg/ kg. In the view of the aforesaid facts and in continuation of our work in the synthesis of biologically active heterocycles [23][24][25][26][27][28][29]. In the view of the aforesaid facts and in continuation of our work in the synthesis of biologically active heterocycles [30][31][32][33][34][35][36],we aimed at synthesis of novel quinoxaline and pteridine derivatives of expected anti-inflammatory activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and studies molecular docking of some new thioxobenzo[g]pteridine derivatives and 1,4-dihydroquinoxaline derivatives with glycosidic moiety

Ghoneim

Elkanzi

Bakr

2018

Journal of Taibah University for Science

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The present work is mainly dedicated to heterocyclic compounds as well as S-glycoside. 1,4dihydroquinoxaline derivatives 3 were obtained from the reaction 2 with carbon disulfide in presence of potassium hydroxide. S-glycoside 4 was prepared from the reaction of compound 3 with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide. Several heterocyclic derivatives containing thioxobenzo[g]pteridine ring systems were obtained starting from ethyl 3-amino-1,4dihydroquinoxaline-2-carboxylate 1. These newly synthesized compounds were docked within the active site of cyclooxygenase-2 (COX-2). The results of this docking study revealed that the new compounds might exhibit good anti-inflammatory activity. The structure of new compounds was demonstrated by elemental analysis, IR, 1 H NMR spectra and mass spectra.

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“…Each member of the epidermal growth factor receptor (EGFR) family plays a key role in normal development, homeostasis, and a variety of pathophysiological conditions 4 . Upon overexpression, they form a mono or heterodimers with other ERB receptors leading to activation of signalling pathways and hence tumour growth 5 , 6 . ERB inhibition can block TK phosphorylation leading to the loss of tumour regulatory functions 5 .…”

Section: Introductionmentioning

confidence: 99%

Benzo[g]quinazolin-based scaffold derivatives as dual EGFR/HER2 inhibitors

Ghorab

Alsaid

Soliman

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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Targeting EGFR has proven to be beneficial in the treatment of several types of solid tumours. So, a series of novel 2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio)-N-substituted acetamide 5–19 were synthesised from the starting material 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4, to be evaluated as dual EGFR/HER2 inhibitors. The target compounds 5–19, were screened for their cytotoxic activity against A549 lung cancer cell line. The percentage inhibition of EGFR enzyme was measured and compared with erlotinib as the reference drug. Compounds 6, 8, 10, and 16 showed excellent EGFR inhibitory activity and were further selected for screening as dual EGFR/HER2 inhibitors. The four selected compounds showed IC50 ranging from 0.009 to 0.026 µM for EGFR and 0.021 to 0.069 µM for the HER2 enzyme. Compound 8 was found to be the most potent in this study with IC50 0.009 and 0.021 µM for EGFR and HER2, respectively.

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Design, synthesis and antitumor activity of novel pyrazolo[3,4-d]pyrimidine derivatives as EGFR-TK inhibitors

Cited by 70 publications

References 30 publications

Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones

Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones

Synthesis and studies molecular docking of some new thioxobenzo[g]pteridine derivatives and 1,4-dihydroquinoxaline derivatives with glycosidic moiety

Benzo[g]quinazolin-based scaffold derivatives as dual EGFR/HER2 inhibitors

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