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...

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Bibliographic Details
Published in:Organic letters 2015-11, Vol.17 (21), p.5476-5479
Main Authors: Kawahara, Teppei, Kagaya, Noritaka, Masuda, Yuichi, Doi, Takayuki, Izumikawa, Miho, Ohta, Kumiko, Hirao, Atsushi, Shin-ya, Kazuo
Format: Article
Language:English
Subjects:
Animals
Forkhead Box Protein O3
Forkhead Transcription Factors - antagonists & inhibitors
Inhibitory Concentration 50
Molecular Structure
Nuclear Magnetic Resonance, Biomolecular
Oxadiazoles - chemistry
Oxadiazoles - isolation & purification
Oxadiazoles - pharmacology
Porifera
Streptomyces - chemistry
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Summary: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.
ISSN:1523-7060
1523-7052
DOI:10.1021/acs.orglett.5b02842