title: Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides.
abstract: The design and synthesis of a series of novel inhibitors of protein kinase C (PKC) is described. These 2,3-bisarylmaleimides were derived from the structural lead provided by the indolocarbazoles, staurosporine and K252a. Optimum activity required the imide NH, both carbonyl groups, and the olefinic bond of the maleimide ring. 2,3-Bisindolylmaleimides were the most active, and the potency of these was improved by a chloro substituent at the 5-position of one indole ring (compound 28, IC50 0.11 microM). In a series of (phenylindolyl)maleimides, nitro compound 74 was most active (IC50 0.67 microM). Naphthalene 19 and benzothiophene 21 showed greater than 100-fold selectivity for inhibition of PKC over the closely related cAMP-dependent protein kinase (PKA).
authors.affiliation: Roche Products Limited, Welwyn Garden City, Herts., U.K.
authors.forename: P D
authors.initials: PD
authors.lastname: Davis
authors.forename: C H
authors.initials: CH
authors.lastname: Hill
authors.forename: G
authors.initials: G
authors.lastname: Lawton
authors.forename: J S
authors.initials: JS
authors.lastname: Nixon
authors.forename: S E
authors.initials: SE
authors.lastname: Wilkinson
authors.forename: S A
authors.initials: SA
authors.lastname: Hurst
authors.forename: E
authors.initials: E
authors.lastname: Keech
authors.forename: S E
authors.initials: SE
authors.lastname: Turner
mesh_terms: D000818:Animals; D001665:Binding Sites; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002227:Carbazoles; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors