Recent developments in anticancer kinase inhibitors based on the pyrazolo[3,4-<i>d</i>]pyrimidine scaffold

Baillache, Daniel J.; Unciti‐Broceta, Asier

doi:10.1039/d0md00227e

Cited by 46 publications

(40 citation statements)

References 137 publications

(185 reference statements)

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“…Acetylcholinesterase from Electrophorus electricus (C2888, Type V-S) was used in this study. In vitro effects on the AChE activity of the target N-alkylated pyrazolo [3,4-d]pyrimidine derivatives (4,10,12,14,16,18,20,22,24,26,28,30,32) were evaluated by the method of Ellman et al [55] TAC was used as the reference drug. All the measurements were repeated three times.…”

Section: Ache Activity Assaymentioning

confidence: 99%

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Synthesis of N‐alkylated pyrazolo[3,4‐d]pyrimidine analogs and evaluation of acetylcholinesterase and carbonic anhydrase inhibition properties

Aydın

Anıl

Demir

2021

Archiv der Pharmazie

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Fused pyrimidines, especially pyrazolo [3,4-d]pyrimidines, are among the most preferred building blocks for pharmacology studies, as they exhibit a broad spectrum of biological activity. In this study, new derivatives of pyrazolo [3,4-d]pyrimidine were synthesized by alkylation of the N1 nitrogen atom. We synthesized 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine 2 from commercially available aminopyrazolopyrimidine 1 using N-iodosuccinimide as an iodinating agent. The synthesis of compound 2 started with nucleophilic substitution of 3-iodo-1H-pyrazolo [3,4-d]pyrimidin-4-amine with R-X (X:-OMs, -Br, -Cl), affording N-alkylated pyrazolo [3,4-d]pyrimidine. We performed this synthesis using a weak inorganic base and the mild temperature was also used for a two-step procedure to generate N-alkylated pyrazolo [3,4-d]pyrimidine derivatives. Also, all compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and the human carbonic anhydrase (hCA) isoforms I and II, with K i values in the range of

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Section: Ache Activity Assaymentioning

confidence: 99%

“…Sapanisertib is an experimental kinase inhibitor, which is currently in clinical trials for several cancer indications. [12] Zaleplon and sildenafil are other FDA-approved drugs containing the pyrazolopyrimidine core structure. [13] The carbonic anhydrases (CAs) play a role in the reversible hydration of CO 2 into bicarbonate and protons.…”

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confidence: 99%

Synthesis of N‐alkylated pyrazolo[3,4‐d]pyrimidine analogs and evaluation of acetylcholinesterase and carbonic anhydrase inhibition properties

Aydın

Anıl

Demir

2021

Archiv der Pharmazie

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“… Structure-activity of some selected CDK-2 inhibitors [ 5 , 6 , 7 , 8 , 36 , 37 ] and structure design of our newly synthesized compounds 3 – 9 . …”

Section: Figures Schemes and Tablesmentioning

confidence: 99%

“…Therefore, there is a need to develop new anti-cancer agents [ 2 , 3 ]. Literature survey indicated that pyrimidine analogs are of considerable interest in drug discovery [ 4 , 5 , 6 , 7 , 8 ]. They possess remarkable biological activity especially as anti-cancer and anti-viral agents due to their resemblance to cellular pyrimidine bases involved in nucleic acids formation.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel 2-Thiouracil-5-Sulfonamide Derivatives as Potent Inducers of Cell Cycle Arrest and CDK2A Inhibition Supported by Molecular Docking

Fatahala

Sayed

Mahgoub

et al. 2021

IJMS

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In an effort to discover potent anticancer agents, 2-thiouracil-5-sulfonamides derivatives were designed and synthesized. The cytotoxic activity of all synthesized compounds was investigated against four human cancer cell lines viz A-2780 (ovarian), HT-29 (colon), MCF-7 (breast), and HepG2 (liver). Compounds 6b,d–g, and 7b showed promising anticancer activity and significant inhibition of CDK2A. Moreover, they were all safe when tested on WI38 normal cells with high selectivity index for cancer cells. Flow cytometric analysis for the most active compound 6e displayed induction of cell growth arrest at G1/S phase (A-2780 cells), S phase (HT-29 and MCF-7 cells), and G2/M phase (HepG2 cells) and stimulated the apoptotic death of all cancer cells. Moreover, 6e was able to cause cycle arrest indirectly through enhanced expression of cell cycle inhibitors p21 and p27. Finally, molecular docking of compound 6e endorsed its proper binding to CDK2A, which clarifies its potent anticancer activity.

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“…Over the past years, some pyrrolo [2,3-d]pyrimidine derivatives were identified as inhibitors of Mer receptor and Src non-receptor tyrosine kinases, isoform of protein kinase B (Akt), mitotic checkpoint kinase (Mps1), Janus kinase 2 (JAK2), and phosphoinositide 3 kinase (PI3K) with promising anticancer activity [25][26][27][28][29][30][31][32][33]. Design strategy in development of purine derivatives as cytostatic agents for kinase inhibition revealed that introduction of cyclic amines improved the activity by forming an additional hydrogen bond to kinase hinge [9,34,35]. In addition, prevalence of halogenated drugs showed that halogen bonds contribute to the stability of protein-ligand complexes [36].…”

Section: Introductionmentioning

confidence: 99%

Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation

et al. 2021

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Novel symmetrical bis-pyrrolo[2,3-d]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung adenocarcinoma (A549), cervical carcinoma (HeLa), ductal pancreatic adenocarcinoma (CFPAC-1) and metastatic colorectal adenocarcinoma (SW620) cells. The use of ultrasound irradiation as alternative energy input in Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) shortened the reaction time, increased the reaction efficiency and led to the formation of exclusively symmetric bis-heterocycles. DFT calculations showed that triazole formation is exceedingly exergonic and confirmed that the presence of Cu(I) ions is required to overcome high kinetic requirements and allow the reaction to proceed. The influence of various linkers and 6-substituted purine and regioisomeric 7-deazapurine on their cytostatic activity was revealed. Among all the evaluated compounds, the 4-chloropyrrolo[2,3-d]pyrimidine monomer 5f with 4,4′-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC50 = 0.79 µM). Annexin V assay results revealed that its strong growth inhibitory activity against CFPAC-1 cells could be associated with induction of apoptosis and primary necrosis. Further structural optimization of bis-chloropyrrolo[2,3-d]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.

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Recent developments in anticancer kinase inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold

Abstract: Pyrazolo[3,4-d]pyrimidines have become of significant interest for the medicinal chemistry community as a privileged scaffold for the development of kinase inhibitors to treat a range of diseases, including cancer.

Cited by 46 publications

References 137 publications

Synthesis of N‐alkylated pyrazolo[3,4‐d]pyrimidine analogs and evaluation of acetylcholinesterase and carbonic anhydrase inhibition properties

Synthesis of N‐alkylated pyrazolo[3,4‐d]pyrimidine analogs and evaluation of acetylcholinesterase and carbonic anhydrase inhibition properties

Synthesis of Novel 2-Thiouracil-5-Sulfonamide Derivatives as Potent Inducers of Cell Cycle Arrest and CDK2A Inhibition Supported by Molecular Docking

Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation

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