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Bromo-substituted indirubins for inhibition of protein kinase-mediated signalling involved in inflammatory mediator release in human monocytes.
- Source :
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Bioorganic chemistry [Bioorg Chem] 2024 Aug; Vol. 149, pp. 107470. Date of Electronic Publication: 2024 May 23. - Publication Year :
- 2024
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Abstract
- Targeting protein kinases that regulate signalling pathways in inflammation is an effective pharmacological approach to alleviate uncontrolled inflammatory diseases. In this context, the natural product indirubin and its 6-bromo-substituted analogue 6-bromoindirubin-3 -glycerol-oxime ether (6BIGOE; 1) were identified as potent inhibitors of glycogen synthase kinase-3β (GSK-3β). These inhibitors suppress the release of pro-inflammatory cytokines and prostaglandins (PG) from human monocytes. However, indirubin derivatives target several protein kinases such as cyclin-dependent kinases (CDKs) which has been a major concern for their application in inflammation therapy. Here, we report on a library of 13 5-bromo-substituted indirubin derivatives that have been designed to improve potency and target selectivity. Side-by-side comparison of reference compound 1 (6BIGOE) with 5-bromo derivatives revealed its isomer 2 (5BIGOE), as the most potent derivative able to supress pro-inflammatory cytokine and PG release in lipopolysaccharide-stimulated human monocytes. Analysis of protein kinase inhibition in intact monocytes, supported by our in silico findings, proposed higher selectivity of 1 for GSK-3β inhibition with lesser potency against CDKs 8 and 9. In contrast, 2 supressed the activity of these CDKs with higher effectiveness than GSK-3β, representing additional targets of indirubins within the inflammatory response. Encapsulation of 1 and 2 into polymer-based nanoparticles (NP) improved their pharmacological potential. In conclusion, the 5- and 6-brominated indirubins 1 and 2 as dual GSK-3β and CDK8/9 inhibitors represent a novel concept for intervention with inflammatory disorders.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Structure-Activity Relationship
Molecular Structure
Inflammation Mediators metabolism
Inflammation Mediators antagonists & inhibitors
Dose-Response Relationship, Drug
Lipopolysaccharides pharmacology
Lipopolysaccharides antagonists & inhibitors
Cytokines metabolism
Cytokines antagonists & inhibitors
Molecular Docking Simulation
Monocytes drug effects
Monocytes metabolism
Indoles pharmacology
Indoles chemistry
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors chemical synthesis
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 149
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38838619
- Full Text :
- https://doi.org/10.1016/j.bioorg.2024.107470