title: Synthesis and protein kinase inhibitory activity of balanol analogues with modified benzophenone subunits.
abstract: A series of analogues of the protein kinase C (PKC) inhibitory natural product balanol which bear modified benzophenone subunits are described. The analogues were designed with the goal of uncovering structure-activity features that could be used in the development of PKC inhibitors with a reduced polar character compared to balanol itself. The results of these studies suggest that most of the benzophenone features found in the natural product are important for obtaining potent PKC inhibitory compounds. However, several modifications were found to lead to selective inhibitors of the related enzyme protein kinase A (PKA), and several specific modifications to the polar structural elements of the benzophenone were found to provide potent PKC inhibitors. In particular, it was found that replacement of the benzophenone carboxylate with bioisosteric equivalents could lead to potent analogues. Further, a tolerance for lipophilic substituents on the terminal benzophenone ring was uncovered. These results are discussed in light of recently available structural information for PKA.
authors.affiliation: Sphinx Laboratories, Lilly Research Laboratories, Eli Lilly and Company, 20 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA. lampe_john_w@lilly.com
authors.forename: John W
authors.initials: JW
authors.lastname: Lampe
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Biggers
authors.forename: Jean M
authors.initials: JM
authors.lastname: Defauw
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Foglesong
authors.forename: Steven E
authors.initials: SE
authors.lastname: Hall
authors.forename: Julia M
authors.initials: JM
authors.lastname: Heerding
authors.forename: Sean P
authors.initials: SP
authors.lastname: Hollinshead
authors.forename: Hong
authors.initials: H
authors.lastname: Hu
authors.forename: Philip F
authors.initials: PF
authors.lastname: Hughes
authors.forename: G Erik
authors.initials: GE
authors.lastname: Jagdmann
authors.forename: Mary George
authors.initials: MG
authors.lastname: Johnson
authors.forename: Yen-Shi
authors.initials: YS
authors.lastname: Lai
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Lowden
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lynch
authors.forename: José S
authors.initials: JS
authors.lastname: Mendoza
authors.forename: Marcia M
authors.initials: MM
authors.lastname: Murphy
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Wilson
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Ballas
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Carter
authors.forename: James W
authors.initials: JW
authors.lastname: Darges
authors.forename: Jefferson E
authors.initials: JE
authors.lastname: Davis
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Hubbard
authors.forename: Mark L
authors.initials: ML
authors.lastname: Stamper
mesh_terms: D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry; D001577:Benzophenones / Q000138:chemical synthesis* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D062385:Hydroxybenzoates / Q000138:chemical synthesis* / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D001577:Benzophenones; D004791:Enzyme Inhibitors; D062385:Hydroxybenzoates; D007527:Isoenzymes; C015405:ophiocordin; D011493:Protein Kinase C