Synthesis and anticancer effects of some novel pyrazolo[3,4-d]pyrimidine derivatives by generating reactive oxygen species in human breast adenocarcinoma cells

Rashad, Aymn E.; Mahmoud, Abeer E.; Ali, Mamdouh M.

doi:10.1016/j.ejmech.2011.01.013

Cited by 80 publications

(32 citation statements)

References 43 publications

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“…Previous reports had indicated that chemotherapeutic agents may be selectively toxic to tumor cells because of increasing oxidant stress due to excess of ROS [33], [55], [56]. In our study, NPRL-Z-1 was shown to induce ROS accumulation and significantly reversed by NAC, a precursor of glutathione (GSH).…”

Section: Discussionsupporting

confidence: 48%

NPRL-Z-1, as a New Topoisomerase II Poison, Induces Cell Apoptosis and ROS Generation in Human Renal Carcinoma Cells

Pan

Xiao

et al. 2014

PLoS ONE

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NPRL-Z-1 is a 4β-[(4″-benzamido)-amino]-4′-O-demethyl-epipodophyllotoxin derivative. Previous reports have shown that NPRL-Z-1 possesses anticancer activity. Here NPRL-Z-1 displayed cytotoxic effects against four human cancer cell lines (HCT 116, A549, ACHN, and A498) and exhibited potent activity in A498 human renal carcinoma cells, with an IC50 value of 2.38 µM via the MTT assay. We also found that NPRL-Z-1 induced cell cycle arrest in G1-phase and detected DNA double-strand breaks in A498 cells. NPRL-Z-1 induced ataxia telangiectasia-mutated (ATM) protein kinase phosphorylation at serine 1981, leading to the activation of DNA damage signaling pathways, including Chk2, histone H2AX, and p53/p21. By ICE assay, the data suggested that NPRL-Z-1 acted on and stabilized the topoisomerase II (TOP2)–DNA complex, leading to TOP2cc formation. NPRL-Z-1-induced DNA damage signaling and apoptotic death was also reversed by TOP2α or TOP2β knockdown. In addition, NPRL-Z-1 inhibited the Akt signaling pathway and induced reactive oxygen species (ROS) generation. These results demonstrated that NPRL-Z-1 appeared to be a novel TOP2 poison and ROS generator. Thus, NPRL-Z-1 may present a significant potential anticancer candidate against renal carcinoma.

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Section: Discussionsupporting

confidence: 48%

NPRL-Z-1, as a New Topoisomerase II Poison, Induces Cell Apoptosis and ROS Generation in Human Renal Carcinoma Cells

Pan

Xiao

et al. 2014

PLoS ONE

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“…For example, capecitabine [14], N-nucleoside and C-nucleoside, are applied in the treatment of metastatic breast cancer and hairy cell leukemia, respectively. Recently, a number of S-glycosides, a new non classical class of nucleosides, have been proved to be potential anticancer agents against many cell lines [17][18][19][20][21][22]. Elgemeie et al described the synthesis of series of heterocyclic thioglycosides, pyridine [33], benzisoquinoline [16] and pyrimidinthione [34] thioglycosides and revealed their potential antitumor activities.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Cytotoxic Evaluation of Novel Heterocyclic Thioglycosides

Gh¹,

Ab²,

Km³

et al. 2014

Med chem

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“…Extensive studies have shown pyrazolo [3,4-d]pyrimidines to have anticancer potential due to multiple target inhibition of epidermal growth factor (EGFR) inhibitors, mammalian target of rapamycin (mTOR) inhibitors [21], Src or dual Src/Abl inhibitors [22], cyclin-dependent kinase (CDK) inhibitors, glycogen synthase kinase-3b (GSK-3b) inhibitors [23][24][25], xanthine oxidase inhibitors through modulating oxygen stress in cancer cells [26]. Some pyrazolo [1,5a]-1,3,5 triazines, as purine bioisosteres, have also shown potent CDK2 inhibitory activity [27]. The inhibitors have been reported to be placed in the ATP pocket of CDK2 receptor.…”

Section: Introductionmentioning

confidence: 99%

“…2) with very promising IC50 values [7]. [3,4-d] pyrimidines derivatives have gained considerable attention due to their reported anticancer and antileukemic activities [9][10][11][12][13]14]. The biological effect is attributed to their cyclin-dependent kinase inhibitor [15][16][17] and tyrosine kinase inhibitory activity [18][19].…”

Section: Introductionmentioning

confidence: 99%

MOLECULAR DOCKING STUDY ON 1H-(3,4d) PYRAZOLO-PYRIMIDINES AS CYCLIN DEPENDANT KINASE (CDK2) INHIBITORS

Phoujdar

Aland

2016

Int J Curr Pharm Sci

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Objective: CDK2 inhibitors are implicated in several carcinomas viz. Carcinoma of lung, bladder, sarcomas and retinoblastoma. Pyrazolopyrimidines, being purine bioisosters inhibit more than one type of kinase. In this study, we are studying some novel derivatives of 1H-pyrazolo [3,4d] pyrimidines not reported earlier. The objective of the present study is an attempt towards design and development of 1H-[3,4-] pyrazolo-pyrimidines as CDK2 inhibitors through rational drug design. Methods:The present study has been done on CDK2 structure, PDB ID, 3WBL, co-crystallized with ligand PDY from RCSB protein data bank. A series of seventeen 1H-Pyrazolo [3,4-d] pyrimidines feasible for synthesis was docked on the said CDK2 receptor using Auto Dock 4 version, 1.5.6. Outputs were exported to discovery studio 3.5 client for visual inspection of the binding modes and interactions of the compounds with amino acid residues in the active sites. Results:The results of docking studies revealed that the present series of 1H-Pyrazolo [3,4-d] pyrimidines is showing significant binding through hydrogen bonding, hydrophobic, pi and Van der waals interactions, similar to the ligand PDY. Some conserved H-bond interactions comparable to bioisosters and compounds presently under human trials were noted. Ki values predicted in silico also suggest that the series will show promising CDK2 inhibitory activity. Conclusion:The series designed and docked can be further developed by synthesis and in vitro and in vivo activity. The receptor inhibitory activity can also be checked by specific receptor assays.

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Synthesis and anticancer effects of some novel pyrazolo[3,4-d]pyrimidine derivatives by generating reactive oxygen species in human breast adenocarcinoma cells

Cited by 80 publications

References 43 publications

NPRL-Z-1, as a New Topoisomerase II Poison, Induces Cell Apoptosis and ROS Generation in Human Renal Carcinoma Cells

NPRL-Z-1, as a New Topoisomerase II Poison, Induces Cell Apoptosis and ROS Generation in Human Renal Carcinoma Cells

Design, Synthesis and Cytotoxic Evaluation of Novel Heterocyclic Thioglycosides

MOLECULAR DOCKING STUDY ON 1H-(3,4d) PYRAZOLO-PYRIMIDINES AS CYCLIN DEPENDANT KINASE (CDK2) INHIBITORS

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