Medicinal attributes of pyrazolo[1,5-a]pyrimidine based scaffold derivatives targeting kinases as anticancer agents

Ismail, Nasser S. M.; Ali, Ghada; Ibrahim, Diaa A.; Elmetwali, Amira M.

doi:10.1016/j.fjps.2016.08.004

Cited by 40 publications

(13 citation statements)

References 99 publications

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“…Moreover, results from the last studies suggest that both ancillary ligand and intercalative ligand influence the degree of binding of these complexes to DNA as a result of which the majority of the metal-pyrazole complexes possessed anti-proliferative activities against cancer cell lines 15–17 . Additionally, various pyrazole and pyrazoline derivatives have been identified as inhibitors of cyclin-dependent kinase 18 and vascular endothelium growth factors 19 . Pyrazoloacridine was identified as a DNA topoisomerase inhibitor.…”

Section: Introductionmentioning

confidence: 99%

A novel series of pyrazole-platinum(II) complexes as potential anti-cancer agents that induce cell cycle arrest and apoptosis in breast cancer cells

Czarnomysy

Surażyński

Muszyńska

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Six novel compounds of platinum(II) with pyrazole derivatives PtPz1–PtPz6 were synthesised and characterised (PtPz1 - [Pt2N-hydroksymethyl-3,5-dimethylpyrazole4(berenil)2]Cl4; PtPz2 - [Pt23,5-dimethylpyrazole4(berenil)2]Cl4; PtPz3 - [Pt23,4-dimethylpyrazole4(berenil)2]Cl4; PtPz4 - [Pt2pyrazole4(berenil)2]Cl4; PtPz5- [Pt25-methylpyrazole4(berenil)2]Cl4; PtPz6 - [Pt2N-ethylpyrazole4(berenil)2]Cl4). The cytotoxic activity of these complexes against MCF-7 and MDA-MB-231 breast cancer cell lines was determined using the MTT assay. Evaluation of apoptosis induction was done with the Annexin V-fluorescein isothiocyanate/propidium iodide assay. In addition, using a flow cytometer, we determined the influence of test compounds on the cell cycle and caspase-3, -8, and -9 activity. The obtained results of caspase activity were confirmed by cell imaging. Moreover, using the flow cytometer, the effects of the test compounds on mitochondrial potential change were assessed. The test results showed that novel pyrazole-platinum(II) complexes exhibited stronger anti-proliferative activity against two breast cancer cell lines than reference cisplatin. Compounds PtPz1, PtPz2, and PtPz3 with methyl substituents at the pyrazole ring showed stronger activity than pyrazole or ethylpyrazole containing complexes. Studies have shown that inhibition of cell survival occurs by arresting the G1 cell cycle and inducing apoptosis. Our analysis associated with the response of MCF-7 and MDA-MB-231 cells to treatment with PtPz1–PtPz6 showed that it leads the cells through the external and intrinsic (mitochondrial) apoptotic pathway via indirect DNA damage.

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Section: Introductionmentioning

confidence: 99%

A novel series of pyrazole-platinum(II) complexes as potential anti-cancer agents that induce cell cycle arrest and apoptosis in breast cancer cells

Czarnomysy

Surażyński

Muszyńska

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…SAR analysis showed that the 2 H -pyrazole scaffold is the crucial pharmacophore for achieving good inhibitory activity, and the substitutions at the 3, 4 and 5-positions of the phenyl ring significantly increased inhibitory activity [ 17 ]. Various pyrazole and pyrazoline derivatives have been identified as inhibitors of cyclin-dependent kinase [ 18 ] heat shock proteins [ 19 ], vascular endothelium growth factors [ 20 ] and P-glycoprotein [ 21 ]. Pyrazoloacridine was identified as a DNA topoisomerase inhibitor via high-throughput screening in clinical research and inhibited malignancy, induced apoptosis in myeloma and leukemia cells and displayed preclinical activity in myeloma and leukemia cells both in vitro and in vivo [ 22 ] .…”

Section: Introductionmentioning

confidence: 99%

A New Series of Cytotoxic Pyrazoline Derivatives as Potential Anticancer Agents that Induce Cell Cycle Arrest and Apoptosis

Wang

Zheng

et al. 2017

Molecules

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A new series of pyrazoline derivatives 1b–12b was designed, synthesized and evaluated for antiproliferative activity against three cancer cell lines (HepG-2, Hela and A549). Additionally, NIH/3T3 cell cytotoxicity were tested and the structure activity relationships (SARs) were also determined. Among these new derivatives, the compounds 3-(4-fluorophenyl)-5-(3,4,5-trimethoxythiophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (1b) and 3-(4-chlorophenyl)-5-(3,4,5-trimethoxythiphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (2b) showed the best activity against HepG-2 cells, with IC50 values of 6.78 μM and 16.02 μM, respectively. They also displayed potent activity against Hela cells; meanwhile, 3-(4-chlorophenyl)-5-(3-bromo-4-hydroxy-5-methoxythiophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (5b) and 3-(4-bromo-phenyl)-5-(3-bromo-4-hydroxy-5-methoxythiophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (6b) were also identified as promising anticancer agents against A549 cells owing to their notable inhibitory effect, compared with cisplatin (IC50 = 29.48 μM). Furthermore, it was also found that compounds 1b and 2b had low cytotoxicity against NIH/3T3 cells and further mechanistic studies revealed that 1b arrested HepG-2 cells cycle at the G2/M phase at high concentrations and induced apoptosis in HepG-2 cells. Moreover, 1b upregulated protein expression level of cleaved caspase-3, cleaved PARP, Bax and p53 and downregulated protein expression level of Bcl-2 in dose-dependent way in HepG-2 cells. Thus, this study indicates that compound 1b might be a promising antitumor drug candidate.

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“…There are various isomeric forms of pyrazolopyrimidines, such as pyrazolo[1,5-a]pyrimidines, pyrazolo[5,1-b]pyrimidines, pyrazolo[3,4-d]pyrimidines and pyrazolo[4,3-d]pyrimidines, which all have found use in drug development and presented potential in antiviral, antimicrobial, anticoccidials, antitumour and anti-inflammatory activities 41 . Pyrazolopyrimidine derivatives have been found to inhibit many protein kinases, such as Src kinase 42 , cyclin-dependent kinases 43,44 , Chk1 Checkpoint kinase 45 , B-Raf protein kinase 46 and Aurora-A kinase 47 , which are considered significant targets for anti-cancer drug development, as the alterations in many kinase activities are involved in cancerous mutations 48 . For example, Kamal A. et al (2013) reported a run of aminobenzothiazole linked pyrazolo[1,5-a]pyrimidine conjugates and demonstrated their anti-cancer ability against 5 human cancer cell lines including A549 (lung), ACHN (renal), DU-145 (prostate), Hela (cervical) and MCF-7 (breast) 49 .…”

Section: Discussionmentioning

confidence: 99%

Synergistic Cytotoxicity Between Cold Atmospheric Plasma and Pyrazolopyrimidinones Against Glioblastoma Cells

Charleton

Devine

et al. 2021

Preprint

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Pyrazolopyrimidinone is a fused nitrogen-containing heterocyclic system, which acts as a core scaffold in many pharmaceutically relevant compounds. Pyrazolopyrimidinones have been demonstrated to be efficient in treating several diseases, including cystic fibrosis, obesity, viral infection and cancer. We have tested the synergistic anti-cancer effects of 15 pyrazolopyrimidinones, synthesised in a two-step process, combined with cold atmospheric plasma (CAP), a novel innovation generating reactive species with other unique chemical and physical effects. We identify two pyrazolopyrimidinones that act as prodrugs and display enhanced reactive-species dependent cytotoxicity when used in combination with cold atmospheric plasma. Synergistic activation was evident for both direct CAP treatment on prodrug loaded tumour cells and indirect CAP treatment of prodrug in media prior to adding to tumour cells. Our results demonstrate the potential of CAP combined with pyrazolopyrimidinones as a programmable cytotoxic therapy against cancer.

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Medicinal attributes of pyrazolo[1,5-a]pyrimidine based scaffold derivatives targeting kinases as anticancer agents

Cited by 40 publications

References 99 publications

A novel series of pyrazole-platinum(II) complexes as potential anti-cancer agents that induce cell cycle arrest and apoptosis in breast cancer cells

A novel series of pyrazole-platinum(II) complexes as potential anti-cancer agents that induce cell cycle arrest and apoptosis in breast cancer cells

A New Series of Cytotoxic Pyrazoline Derivatives as Potential Anticancer Agents that Induce Cell Cycle Arrest and Apoptosis

Synergistic Cytotoxicity Between Cold Atmospheric Plasma and Pyrazolopyrimidinones Against Glioblastoma Cells

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