scholarly journals SYNTHETIC APPROACHES TO HYDROGENIZED PYRIDYL[b]AZEPINE AND THEIR BENZENELYLATED ANALOGUES

2020 ◽  
Vol 86 (8) ◽  
pp. 101-110
Author(s):  
Ivanna Danyliuk ◽  
Mykhailo Vovk

Pyrido[b]azepines are represented in the literature by four types of isomeric structures: pyrido[3,2-b] azepines, pyrido[2,3-b]azepines, pyrido[3,4-b] azepines and pyrido[4,3-b ]azepines. They belong to the structural analogues of 1-benzazepine - an attractive class of heterocycles with a strong pharmacological profile. They are also used as important molecular platforms in the construction of bioactive compounds. Analysis of the literature has shown that compounds that contain the pyrido[b]azepine fragment demonstrate antiviral, antimicrobial, and antitumor activity. They are knownas effective inhibitors of R1P1 kinase, ubiquitin- specific proteases (USPS), cyclin-dependent kinase (CDKS), and glycogen synthase kinase 3 (GSK-3), TRPM8 protein, and angiotensin I type 2 (AT2) receptors. Over the last decade, promising pharmacological properties of pyrido[b]azepine derivatives stimulated the development of fundamentally new methods of their synthesis as well as the improvement of known synthetic approaches. In general, among the various methods for the synthesis of hydrogenated pyrido[b] azepines and their benzanelated analogues, priority is currently given to approaches that include the formation of an azepine cycle via the intermolecular formation of C-N and C-C bonds. These mainly include catalytic cyclizations using cobalt, palladium, and rhodium compounds. Reactions of intramolecular radical difluoromethylarylation and diauryl peroxide-initiated radical azepine analelenization of the pyridine fragment are also of great importance. An interesting method for the synthesis of pyrido [2,3-b] azepin-5-one derivatives was developed on the basis of the Friedel-Crafts intramolecular cycloalkylations reaction.

2013 ◽  
Vol 27 (7) ◽  
pp. 1078-1090 ◽  
Author(s):  
Ilham El Khattabi ◽  
Arun Sharma

Abstract The reduction in the expression of glucose-responsive insulin gene transcription factor MafA accompanies the development of β-cell dysfunction under oxidative stress/diabetic milieu. Humans with type 2 diabetes have reduced MafA expression, and thus preventing this reduction could overcome β-cell dysfunction and diabetes. We previously showed that p38 MAPK, but not glycogen synthase kinase 3 (GSK3), is a major regulator of MafA degradation under oxidative stress. Here, we examined the mechanisms of this degradation and whether preventing MafA degradation under oxidative stress will overcome β-cell dysfunction. We show that under oxidative and nonoxidative conditions p38 MAPK directly binds to MafA and triggers MafA degradation via ubiquitin proteasomal pathway. However, unlike nonoxidative conditions, MafA degradation under oxidative stress depended on p38 MAPK-mediated phosphorylation at threonine (T) 134, and not T57. Furthermore the expression of alanine (A) 134-MafA, but not A57-MafA, reduced the oxidative stress-mediated loss of glucose-stimulated insulin secretion, which was independent of p38 MAPK action on protein kinase D, a regulator of insulin secretion. Interestingly, the expression of proteasomal activator PA28γ that degrades GSK3-phosphorylated (including T57) MafA was reduced under oxidative stress, explaining the dominance of p38 MAPK over the GSK3 pathway in regulating MafA stability under oxidative stress. These results identify two distinct pathways mediating p38 MAPK-dependent MafA degradation under oxidative and nonoxidative conditions and show that inhibiting MafA degradation under oxidative stress ameliorates β-cell dysfunction and could lead to novel therapies for diabetes.


2020 ◽  
Vol 16 (11) ◽  
pp. 893-899
Author(s):  
Selvaraj Jayaraman ◽  

Type 2 diabetes mellitus (T2DM) is linked with Glycogen synthase kinase-3 β.Therefore, it is ofinterest to document molecular docking analysis data of compounds from Justica adhatoda L with glycogen synthase kinase-3 β. We report the binding features of ethambutol, pyrazinamide, stigmasterol and vasicoline with GSK-3 β.


Sign in / Sign up

Export Citation Format

Share Document