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Design and synthesis of novel 1,3,5-triphenyl pyrazolines as potential anti-inflammatory agents through allosteric inhibition of protein kinase Czeta (PKCζ)
- Source :
- MedChemComm. 9:1076-1082
- Publication Year :
- 2018
- Publisher :
- Royal Society of Chemistry (RSC), 2018.
-
Abstract
- Much light has been shed on the vital role of protein kinase Czeta (PKCζ) in NF-κB activation and the potential use of PKCζ inhibitors as anti-inflammatory agents. We previously reported a series of 1,3,5-trisubstituted pyrazolines as potent and selective allosteric inhibitors of PKCζ; in that series of compounds, the phenolic OH at the 5-phenyl was essential for binding to the PKCζ PIF pocket. In the present study, we surprisingly found that replacing it by a halogen and at the same time moving the OH to the 3-phenyl still resulted in active compounds. An extension of this class of compounds with a new focused library is presented herein, where the phenolic OH at the 5-phenyl, which was reported to be an irreplaceable feature for activity, was moved to the 3-phenyl and replaced by halogen. The new set of compounds maintained the same level of potency against PKCζ and selectivity against PKC isoforms, and showed reduced potency against the PIF pocket mutant PKCζ[Val297Leu]. Of note, the repositioning of the key functional groups resulted in a marked enhancement of cellular potency. One of the most potent new PKCζ inhibitors, 2h, was able to suppress NO production in RAW 264.7 macrophage cells with 8 times higher efficacy than the previous series, and inhibited the NF-κB transcriptional activity in U937 cells with a sub-micromolar IC(50).
- Subjects :
- 0301 basic medicine
Pharmacology
U937 cell
Chemistry
medicine.drug_class
Organic Chemistry
Allosteric regulation
Mutant
Pharmaceutical Science
Biochemistry
Anti-inflammatory
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
030220 oncology & carcinogenesis
Drug Discovery
medicine
Molecular Medicine
Potency
No production
Protein kinase A
IC50
Subjects
Details
- ISSN :
- 20402511 and 20402503
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- MedChemComm
- Accession number :
- edsair.doi.dedup.....a445a9523950478caa074e09a3305fb3