Development of novel adenosine monophosphate-activated protein kinase activators.
In light of the unique ability of thiazolidinediones to mediate peroxisome proliferator-activated receptor (PPAR)gamma-independent activation of adenosine monophosphate-activated protein kinase (AMPK) and suppression of interleukin (IL)-6 production, we conducted a screening of an in-house, thiazolidinedione-based focused compound library to identify novel agents with these dual pharmacological activities. Cell-based assays pertinent to the activation status of AMPK and mammalian homologue of target of rapamycin (i.e., phosphorylation of AMPK and p70 ribosomal protein S6 kinase, respectively) and IL-6/IL-6 receptor signaling (i.e., IL-6 production and signal transducer and activator of transcription 3 phosphorylation, respectively) in lipopolysaccharide (LPS)-stimulated THP-1 human macrophages were used to screen this compound library, which led to the identification of compound 53 (N-{4-[3-(1-methyl-cyclohexylmethyl)-2,4-dioxo-thiazolidin-5-ylidene-methyl]-phenyl}-4-nitro-3-trifluoro-methyl-benzenesulfonamide) as the lead agent. Evidence indicates that this drug-induced suppression of LPS-stimulated IL-6 production was attributable to AMPK activation. Furthermore, compound 53-mediated AMPK activation was demonstrated in C-26 colon adenocarcinoma cells, indicating that it is not a cell line-specific event.
Guh
Jih-Hwa
JH
Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, 336 Parks Hall, 500 West 12th Avenue, Columbus, Ohio 43210, USA.
Chang
Wei-Ling
WL
Yang
Jian
J
Lee
Su-Lin
SL
Wei
Shuo
S
Wang
Dasheng
D
Kulp
Samuel K
SK
Chen
Ching-Shih
CS
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009010:Monte Carlo Method; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
D055372:AMP-Activated Protein Kinases; D020536:Enzyme Activators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D013449:Sulfonamides; D045162:Thiazolidinediones; C549054:N-(4-(3-(1-methyl-cyclohexylmethyl)-2,4-dioxothiazolidin-5-ylidenemethyl)phenyl)-4-nitro-3-trifluoromethylbenzenesulfonamide; D000096926:Benzenesulfonamides