Synthesis and protein kinase inhibitory activity of balanol analogues with modified benzophenone subunits.
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.
Lampe
John W
JW
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
Biggers
Christopher K
CK
Defauw
Jean M
JM
Foglesong
Robert J
RJ
Hall
Steven E
SE
Heerding
Julia M
JM
Hollinshead
Sean P
SP
Hu
Hong
H
Hughes
Philip F
PF
Jagdmann
G Erik
GE
Johnson
Mary George
MG
Lai
Yen-Shi
YS
Lowden
Christopher T
CT
Lynch
Michael P
MP
Mendoza
José S
JS
Murphy
Marcia M
MM
Wilson
Joseph W
JW
Ballas
Lawrence M
LM
Carter
Kiyomi
K
Darges
James W
JW
Davis
Jefferson E
JE
Hubbard
Frederick R
FR
Stamper
Mark L
ML
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
D001381:Azepines; D001577:Benzophenones; D004791:Enzyme Inhibitors; D062385:Hydroxybenzoates; D007527:Isoenzymes; C015405:ophiocordin; D011493:Protein Kinase C