Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142

Teppei Kawahara; Noritaka Kagaya; Yuichi Masuda; Takayuki Doi; Miho Izumikawa; Kumiko Ohta; Atsushi Hirao; Kazuo Shin-Ya

doi:10.1021/acs.orglett.5b02842

Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142

Teppei Kawahara, Noritaka Kagaya, Yuichi Masuda, Takayuki Doi, Miho Izumikawa, Kumiko Ohta, Atsushi Hirao, Kazuo Shin-Ya

PHA - Molecular Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	5476-5479
Number of pages	4
Journal	Organic Letters
Volume	17
Issue number	21
DOIs	https://doi.org/10.1021/acs.orglett.5b02842
Publication status	Published - 2015 Nov 6

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title = "Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142",

abstract = "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.",

author = "Teppei Kawahara and Noritaka Kagaya and Yuichi Masuda and Takayuki Doi and Miho Izumikawa and Kumiko Ohta and Atsushi Hirao and Kazuo Shin-Ya",

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T1 - Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142

AU - Kawahara, Teppei

AU - Kagaya, Noritaka

AU - Masuda, Yuichi

AU - Doi, Takayuki

AU - Izumikawa, Miho

AU - Ohta, Kumiko

AU - Hirao, Atsushi

AU - Shin-Ya, Kazuo

PY - 2015/11/6

Y1 - 2015/11/6

N2 - 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.

AB - 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.

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JF - Organic Letters

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Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142

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