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Journal ArticleDOI

Synthesis and evaluation of pyrazolo[3,4-b]pyridines and its structural analogues as TNF-α and IL-6 inhibitors

TL;DR: Three different series of pyrazolo[3,4-b]pyridines and their structural analogues are synthesized using novel synthetic strategy involving one-pot condensation of 5, 6-dihydro-4H-pyran-3-carbaldehyde/2-formyl-3, 4,6-tri-O-methyl-D-glucal/chromone-3
About: This article is published in Bioorganic & Medicinal Chemistry.The article was published on 2008-08-01. It has received 80 citations till now. The article focuses on the topics: Glucal & Chemical synthesis.
Citations
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Journal ArticleDOI
TL;DR: 3s was obtained as lead compound with promising anticancer, anti-inflammatory and antioxidant activities and was confirmed to be nontoxic by in vitro cytotoxicity study.

258 citations

Journal ArticleDOI
TL;DR: These analyses would assist medicinal chemists to design novel and potent IL-6 production and signaling inhibitors, through knowledge- and/or computer-based approaches, for the treatment of complex multifactorial diseases.

183 citations

Journal ArticleDOI
TL;DR: QSAR study revealed that the presence of electron-withdrawing groups in B-ring and electron-donating groups in A-ring of chalcones was important for inhibition of LPS-induced IL-6 expression, and showed a series of anti-inflammatory chalcone derivatives with potential therapeutic effects in inflammatory diseases.
Abstract: Major anti-inflammatory agents, steroids and cyclooxygenase, were proved to have serious side effects. Here, a series of chalcone derivatives were synthesized and screened for anti-inflammatory activities. QSAR study revealed that the presence of electron-withdrawing groups in B-ring and electron-donating groups in A-ring of chalcones was important for inhibition of LPS-induced IL-6 expression. Further, compounds 22, 23, 26, 40, and 47 inhibited TNF-α and IL-6 release in a dose-dependent manner and decreased LPS-induced TNF-α, IL-1β, IL-6, IL-12, and COX-2 mRNA production. Mechanistically, compounds 23 and 26 interfered with JNK/NF-κB signaling and dose-dependently prevented ERK and p38 activation. In addition, 23 and 26 exhibited a significant protection against LPS-induced death and were able to block high glucose-activated cytokine profiles in macrophages. Together, these data show a series of anti-inflammatory chalcones with potential therapeutic effects in inflammatory diseases.

179 citations

Journal ArticleDOI
TL;DR: It is possible to develop pharmacologically relevant cytotoxic agents by specifically inhibiting CDK2 activity with lesser toxicity than traditional chemotherapeutic agents by targeting a binding pocket other than ATP.
Abstract: Cyclin-dependent kinase-2 (CDK2) is a member of protein kinase family. It plays an important role in regulating various events of eukaryotic cell division cycle. Accumulated evidences indicated that over expression of CDK2 should cause the abnormal regulation of cell-cycle, which would be directly associated with hyperproliferation in cancer cells. Therefore, CDK2 was regarded as a potentially therapeutic target for cancer therapy. Knowledge of crystallography and availability of X-ray crystal structure of CDK2 have enabled us to understand the mode of CDK2 inhibition, which facilitated the development of numerous CDK2 inhibitors. Some of the CDK2 inhibitors were investigated clinically for their potential as anti-cancer agents. In this review, we present the structure, functions and activation of CDK2 by cyclin binding with special focus on recent advances in the development of different classes of CDK2 inhibitors. We also summarize different strategies to achieve subtype specificity either by targeting a binding pocket other than ATP, i.e. allosteric ligand binding site or by natural protein inhibitors capable to disrupt CDK2-cyclin complexes. It is possible to develop pharmacologically relevant cytotoxic agents by specifically inhibiting CDK2 activity with lesser toxicity than traditional chemotherapeutic agents.

128 citations

Journal ArticleDOI
TL;DR: N-Acyl-N'-substituted hydrazines can also react with 2-bromoarylcarbonylic compounds at 60-125 °C under the catalysis of CuI/4-hydroxy-l-proline to provide 1-aryl-1H-indazoles.

100 citations

References
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Journal ArticleDOI
TL;DR: Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6, 7-dimethyl-2-( 4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.
Abstract: The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.

165 citations

Journal ArticleDOI
TL;DR: Three series of 4-anilino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic esters were synthesized as part of a program to study potential anti-Leishmania drugs and showed the 3'-diethylaminomethyl-substituted compounds as the most active.
Abstract: Three series of 4-anilino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic esters were synthesized as part of a program to study potential anti-Leishmania drugs. These compounds were obtained by a condensation reaction of 4-chloro-1H-pyrazolo[3,4-b]pyridine with several aniline derivatives. Some of them were also obtained by an alternative pathway involving a Mannich-type reaction. The hydrophobic parameter, log P, was determined by shake-flask methodology, and using the Hansch−Fujita addictive hydrophobic fragmental constants. These compounds were tested against promastigote forms of Leishmania amazonensis. The very promising results showed the 3‘-diethylaminomethyl-substituted compounds as the most active [IC50 = 0.39 (21) and 0.12 μM (22)]. Molecular modeling, using semiempirical AM1 method, predicted the most active compounds through the low-energy conformers superimposition on amodiaquine structure. QSAR equations, derived from the IC50 values against L. amazonensis, showed the hydrophobic (log P) and Sterimo...

164 citations

Journal ArticleDOI
TL;DR: Recent advances in chemokinc physiology and their potential role in the pathogenesis of mucosal inflammation are reviewed and the potential for the use of chemokine or Chemokine receptor antagonists as novel therapies for inflammatory bowel disease is discussed.
Abstract: Chemokines represent a large family of small cytokines, the main function of which is the attraction of leukocytes to different tissues. Several chemokines and their receptors have been shown to play a critical role in lymphoid development, mucosal immunity, and inflammation. In this article we review recent advances in chemokine physiology and their potential role in the pathogenesis of mucosal inflammation. We also discuss the potential for the use of chemokine or chemokine receptor antagonists as novel therapies for inflammatory bowel disease.

116 citations

Journal ArticleDOI
TL;DR: Some new 2-alkoxy-3-cyano-4,6-diarylpyridines 3,4 were synthesized by condensation of different alpha,beta-unsaturated ketones 1 with malononitrile 2, followed by cyclization in sodium alkoxide/alcohol system.

112 citations

Journal ArticleDOI
TL;DR: It is shown that TNF-alpha unveils a previously unknown capacity of neutrophils to migrate to CCL3 through the intervention of Mac-1, and ERK 1/2 p44 may represent a selective target for the pharmacologic manipulation of neutophil-mediated adverse activities in T NF-alpha-mediated inflammatory states.

106 citations

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