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Sci Rep. 2018 Jan 23;8(1):1400. doi: 10.1038/s41598-018-19664-9.

New 5-Aryl-Substituted 2-Aminobenzamide-Type HDAC Inhibitors with a Diketopiperazine Group and Their Ameliorating Effects on Ischemia-Induced Neuronal Cell Death.

Author information

1
Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35, Yamate-cho, Suita, Osaka, 564-8680, Japan.
2
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan.
3
Department of Neurology, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan. sasaki@neurol.med.osaka-u.ac.jp.
4
Department of Neurology, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
5
Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35, Yamate-cho, Suita, Osaka, 564-8680, Japan. suesato@gaia.eonet.ne.jp.
6
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan. suesato@gaia.eonet.ne.jp.

Abstract

We previously synthesized new 5-thienyl-substituted 2-aminobenzamide-type HDAC1, 2 inhibitors with the (4-ethyl-2,3-dioxopiperazine-1-carboxamido) methyl group. K-560 (1a) protected against neuronal cell death in a Parkinson's disease model by up-regulating the expression of XIAP. This finding prompted us to design new K-560-related compounds. We examined the structure activity relationship (SAR) for the neuronal protective effects of newly synthesized and known K-560 derivatives after cerebral ischemia. Among them, K-856 (8), containing the (4-methyl-2,5-dioxopiperazin-1-yl) methyl group, exhibited a promising neuronal survival activity. The SAR study strongly suggested that the attachment of a monocyclic 2,3- or 2,5-diketopiperazine group to the 2-amino-5-aryl (but not 2-nitro-5-aryl) scaffold is necessary for K-560-related compounds to exert a potent neuroprotective effect.

PMID:
29362442
PMCID:
PMC5780423
DOI:
10.1038/s41598-018-19664-9
[Indexed for MEDLINE]
Free PMC Article

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