Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142.
JBIR-141 (1) and JBIR-142 (2) were discovered as potent Foxo3a inhibitors that consist of three quite unique substructures, a 1-((dimethylamino)ethyl)-5-methyl-4,5-dihydrooxazole-4-carboxylic acid that is originated from Ala-Thr amino acid residues, a 3-acetoxy-4-amino-7-(hydroxy(nitroso)amino)-2,2-dimethylheptanoic acid, and an α-acyl tetramic acid fused with a 2-methylpropan-1-ol moiety. Their structures involving absolute configurations were determined by spectroscopic data, chemical degradation, anisotropy methods, and LC-MS analyses of diastereomeric derivatives. Compounds 1 and 2 exhibited specific inhibition against Foxo3a transcriptional activity with IC50 values of 23.1 and 166.2 nM, respectively.
Japan Biological Informatics Consortium (JBIC), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
Teppei
T
Kawahara
National Institute of Advanced Industrial Science and Technology (AIST) , 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
Noritaka
N
Kagaya
Graduate School of Pharmaceutical Sciences, Tohoku University , 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
Yuichi
Y
Masuda
Graduate School of Pharmaceutical Sciences, Tohoku University , 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
Takayuki
T
Doi
Japan Biological Informatics Consortium (JBIC), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
Miho
M
Izumikawa
Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University , Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Kumiko
K
Ohta
Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University , Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Atsushi
A
Hirao
National Institute of Advanced Industrial Science and Technology (AIST) , 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
Kazuo
K
Shin-ya
D000818:Animals; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010069:Oxadiazoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D011161:Porifera; D013302:Streptomyces / Q000737:chemistry
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C000605298:JBIR-141; C000605299:JBIR-142; D010069:Oxadiazoles