Synthesis and Protein Kinase C Inhibitory Activities of Acyclic Balanol Analogs That Are Highly Selective for Protein Kinase C over Protein Kinase A

• Published in: Journal of medicinal chemistry Vol. 39; no. 26; pp. 5215 - 5227
• Main Authors: Defauw, Jean M., Murphy, Marcia M., Jagdmann, G. Erik, Hu, Hong, Lampe, John W., Hollinshead, Sean P., Mitchell, Thomas J., Crane, Heidi M., Heerding, Julia M., Mendoza, José S., Davis, Jefferson E., Darges, James W., Hubbard, Frederick R., Hall, Steven E.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.12.1996; Amer Chemical Soc
• Subjects: Animals; Azepines - chemistry; Azepines - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Chemistry, Medicinal; Cyclic AMP-Dependent Protein Kinases - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hydroxybenzoates - chemistry; Hydroxybenzoates - pharmacology; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Kinase C - antagonists & inhibitors; Rats; Recombinant Proteins - antagonists & inhibitors; Science & Technology; Substrate Specificity; POTENT; DESIGN; INVITRO; BIOLOGICAL-ACTIVITY; Benzophenone derivatives; Protein kinase C; Sulfonamide; Enzyme; Transferases; Enzyme inhibitor; In vitro; Structure activity relation; Carboxylic acid; Phenols; Benzenic compound; S configuration; Neutrophil; Chemical synthesis; Monocyclic compound; Cyclopentane derivatives; Anti stereoisomer
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960581w

A series of balanol analogs in which the perhydroazepine ring and the p-hydroxybenzamide moiety were combined into an acyclic linked unit have been prepared and evaluated for their inhibitory properties against the serine/threonine kinase PKC. Several low-micromolar to low-nanomolar inhibitors of the α, βI, βII, γ, δ, ε, and η PKC isozymes were prepared. In general, these acyclic balanol analogs were found to be highly selective for PKC over the serine/threonine kinase PKA. The type and number of atoms linking the benzophenone ester to the p-hydroxyphenyl group necessary for optimal PKC inhibition were investigated. The most potent compounds contained a three-carbon linker in which the carboxamide moiety of balanol had been replaced by a methylene group. The effect of placing substituents on the three-carbon chain was also investigated. The preferred compounds contained either a 2-benzenesulfonamido (6b) or a 1-methyl (21b) substituent. The preferred compounds 6b and 21b were tested against a panel of serine/threonine kinases and found to be highly selective for PKC. The more active enantiomer of 6b, (S)-12b, was 3−10-fold more active than the R-enantiomer against the PKC isozymes. The effect of making the analogs more rigid by making the three-carbon chain part of a five-membered ring, but with retention of the methylene replacement for the carboxamide moiety, led to potent PKC inhibitors including anti-substituted pyrrolidine analog 35b and the most potent PKC inhibitor in the series, anti-substituted cyclopentane analog 29b. The anti cyclopentane analog 29b was a low-micromolar inhibitor of the PMA-induced superoxide burst in neutrophils, and its carboxylic ester was a high-nanomolar inhibitor of neutrophils. Finally esterification of 21b, (S)-12b, and 35b turned these potent PKC inhibitors into low-micromolar inhibitors of neutrophils.