Acyclic N-(azacycloalkyl)bisindolylmaleimides: isozyme selective inhibitors of PKCβ

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 11; pp. 1857 - 1859
• Main Authors: Faul, Margaret M, Gillig, James R, Jirousek, Michael R, Ballas, Lawrence M, Schotten, Theo, Kahl, Astrid, Mohr, Michael
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 02-06-2003; Elsevier
• Subjects: Biological and medical sciences; General and cellular metabolism. Vitamins; Medical sciences; Pharmacology. Drug treatments; Endocrinopathy; Protein kinase C; Enzyme; Nitrogen heterocycle; Isozyme; Transferases; Diabetes mellitus; Enzyme inhibitor; Selectivity; In vitro; Pyridine derivatives; Pyrrole derivatives; Imide; Signal transduction; Structure activity relation; Piperidine derivatives; Bicyclic compound; Complication; Aromatic compound; Indole derivatives; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00286-5

The synthesis and structure–activity relationship (SAR) trends of a new class of
N-(azacycloalkyl)bisindolylmaleimides
1, acyclic derivatives of staurosporine, is described. The representative compound for this series (
1e) exhibits an IC
50 of 40–50 nM against the human PKCβ
1 and PKCβ
2 isozymes and selectively inhibits the PKCβ isozymes in comparison to other PKC isozymes (α, γ, δ, ε, λ, and η). The series is also kinase selective for PKC in comparison to other ATP-dependent kinases. A comparison of the PKC isozyme and kinase activity of the series is made to the kinase inhibitor staurosporine.
The synthesis and structure–activity relationship (SAR) trends of a new class of
N-(azacycloalkyl)bisindolylmaleimides
1, acyclic derivatives of staurosporine, will be described and a comparison to the natural product provided.