Targeting tumor cells with pyrazolo[3,4-d]pyrimidine scaffold: A literature review on synthetic approaches, structure activity relationship, structural and target-based mechanisms

Abdelgawad, Mohamed A.; Elkanzi, Nadia A. A.; Nayl, A.A.; Musa, Arafa; Alotaibi, Nasser Hadal; Arafa, Wael A. A.; Gomha, Sobhi M.; Bakr, Rania B.

doi:10.1016/j.arabjc.2022.103781

Cited by 18 publications

(8 citation statements)

References 135 publications

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“…Protein kinases represent a large group of structurally related enzymes that are essential and regulate cell cycle progression involved in cell division 1–3 . Cyclin-dependent kinases (CDKs) are serine-threonine kinases responsible for cell cycle regulation and cell differentiation 2 . Cyclin-dependent kinases (CDK) are mainly responsible for the phosphorylation process of proteins 4–6 .…”

Section: Introductionmentioning

confidence: 99%

“…Cyclin-dependent kinases (CDK) are mainly responsible for the phosphorylation process of proteins 4–6 . Cyclin is the regulatory protein bound by CDK leading to ATP binding region modification 2 . CDKs in absence of cyclin have less activity where the activation loop (known as T-loop) blocks the cleft, and the key amino acid residues are not optimally positioned for ATP binding 2 .…”

Section: Introductionmentioning

confidence: 99%

“…Cyclin is the regulatory protein bound by CDK leading to ATP binding region modification 2 . CDKs in absence of cyclin have less activity where the activation loop (known as T-loop) blocks the cleft, and the key amino acid residues are not optimally positioned for ATP binding 2 . CDK2 has a catalytic effect in cyclin-dependent protein kinase complex 7 , 8 .…”

Section: Introductionmentioning

confidence: 99%

“…Hence, the control of CDK dependent cell cycle is essential for tumour progression management. Where overexpression of CDK enzymes occurs in cancer 2 . As uncontrolled CDK2 activation in human cancer is associated with overexpression of cyclins A and E in many human cancers 12 .…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity

Mandour

Nassar

Aal

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives ( 4–15 ) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8 , 14 , and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC 50 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity

Mandour

Nassar

Aal

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The abovementioned findings and our previous studies related to the discovery of novel bioactive agents − encouraged us to construct novel quinoxaline derivatives and assess these novel candidates for their insecticidal potential against Aphis craccivora. Our design based upon combining the quinoxaline ring with the widely documented insecticidal pyrimidine heterocycle and/or thiazolidinone in one hybrid to obtain pyrimido[1,2- a ]quinoxaline derivatives ( 26 – 30 ), 35 – 38 , and thiazolidin-3-yl-1,4-dihydroquinoxaline ( 15 – 20 ) aims to increase the insecticidal activity and capacity to destroy Aphis craccivora as explained in Figure .…”

Section: Introductionmentioning

confidence: 99%

Green Design, Synthesis, and Molecular Docking Study of Novel Quinoxaline Derivatives with Insecticidal Potential against Aphis craccivora

et al. 2022

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An efficient and environmentally friendly method was established for designing novel 3-amino-1,4-dihydroquinoxaline-2-carbonitrile ( 1 ) via the reaction of bromomalononitrile and benzene-1,2-diamine under microwave irradiation in an excellent yield (93%). This targeted amino derivative was utilized for the construction of a series of Schiff bases ( 8 – 13 ). A new series of thiazolidinone derivatives ( 15 – 20 ) were synthesized in high yields (89–96%) via treatment of thioglycolic acid with Schiff bases ( 8 – 13 ) under microwave irradiation in high yields (89–96%). Moreover, new pyrimidine derivatives ( 26 – 30 and 35 – 38 ) were prepared by treatment of compound 1 with arylidenes ( 21 – 25 ) and/or alkylidenemalononitriles ( 31 – 34 ) using piperidine as a basic catalyst under microwave conditions. Based on elemental analyses and spectral data, the structures of the new assembled compounds were determined. The newly synthesized quinoxaline derivatives were screened and studied as an insecticidal agent against Aphis craccivora . The obtained results indicate that compound 16 is the most toxicological agent against nymphs of cowpea aphids ( Aphis craccivora ) compared to the other synthesized pyrimidine and thiazolidinone derivatives. The molecular docking study of the new quinoxaline derivatives registered that compound 16 had the highest binding score (−10.54 kcal/mol) and the thiazolidinone moiety formed hydrogen bonds with Trp143.

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Design, Synthesis, Docking Study of Pyrazolohydrazinopyrimidin‐4‐one Derivatives and Their Application as Antimicrobials

Bakr

Alolyyan

Elkanzi

et al. 2023

Chemistry & Biodiversity

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New series of pyrazoles 4a-c and pyrazolopyrimidines 5a -f had been constructed. The newly synthesized compounds were assessed for their antimicrobial activity towards E. coli and P. aeruginosa (gram -ve bacteria), B. subtilis and S. aureus (gram + ve bacteria) and A. flavus and C. albicans (representative of fungi). The pyrazolylpyrimidine-2,4-dione derivative 5b is the most active candidate against B. subtilis (MIC = 60 μg/mL) and P. aeruginosa (MIC = 45 μg/mL). Regarding antifungal potential, compound 5f was the most effective against A. flavus (MIC = 33 μg/mL). Similarly, compound 5c displayed strong antifungal activity towards C. Albicans (MIC = 36 μg/mL) in reference to amphotericin B (MIC = 60 μg/mL). Finally, the novel compounds had been docked inside dihydropteroate synthase (DHPS) to suggest the binding mode of these compounds.

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Targeting tumor cells with pyrazolo[3,4-d]pyrimidine scaffold: A literature review on synthetic approaches, structure activity relationship, structural and target-based mechanisms

Cited by 18 publications

References 135 publications

Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity

Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity

Green Design, Synthesis, and Molecular Docking Study of Novel Quinoxaline Derivatives with Insecticidal Potential against Aphis craccivora

Design, Synthesis, Docking Study of Pyrazolohydrazinopyrimidin‐4‐one Derivatives and Their Application as Antimicrobials

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