Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists

Daisuke Kajita; Masaharu Nakamura; Yotaro Matsumoto; Minoru Ishikawa; Yuichi Hashimoto; Shinya Fujii

doi:10.1016/j.bmcl.2015.05.045

Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists

Daisuke Kajita, Masaharu Nakamura, Yotaro Matsumoto, Minoru Ishikawa, Yuichi Hashimoto, Shinya Fujii

PHA - Pharmacy

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

12 Citations (Scopus)

Abstract

Abstract We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we investigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and synthesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing PPARα agonist, and evaluated their PPARα/δ/γ agonistic activity. We found that diethylsilyl derivative 20 exhibited PPARα/δ agonistic activity, and we also obtained a PPARδ-selective agonist, 32. Our results suggest that incorporation of silyl functionality is a useful option for structural development of biologically active compounds.

Original language	English
Article number	22735
Pages (from-to)	3350-3354
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2015.05.045
Publication status	Published - 2015 Jul 3

Keywords

PPAR
Peroxisome proliferator-activated receptor
Sila-substitution
Silicon
cis-Olefin mimetic

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2015.05.045

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Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists. / Kajita, Daisuke; Nakamura, Masaharu; Matsumoto, Yotaro et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 25, No. 16, 22735, 03.07.2015, p. 3350-3354.

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

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abstract = "Abstract We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we investigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and synthesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing PPARα agonist, and evaluated their PPARα/δ/γ agonistic activity. We found that diethylsilyl derivative 20 exhibited PPARα/δ agonistic activity, and we also obtained a PPARδ-selective agonist, 32. Our results suggest that incorporation of silyl functionality is a useful option for structural development of biologically active compounds.",

keywords = "PPAR, Peroxisome proliferator-activated receptor, Sila-substitution, Silicon, cis-Olefin mimetic",

author = "Daisuke Kajita and Masaharu Nakamura and Yotaro Matsumoto and Minoru Ishikawa and Yuichi Hashimoto and Shinya Fujii",

note = "Funding Information: This work was partially supported by Platform for Drug Discovery, Informatics, and Structural Life Science , and Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science, and Technology , Japan, and the Japan Society for the Promotion of Science (KAKENHI Grant No. 26293025 (Y.H.) and No. 25460146 (S.F.)). Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd.",

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T1 - Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists

AU - Kajita, Daisuke

AU - Nakamura, Masaharu

AU - Matsumoto, Yotaro

AU - Ishikawa, Minoru

AU - Hashimoto, Yuichi

AU - Fujii, Shinya

N1 - Funding Information: This work was partially supported by Platform for Drug Discovery, Informatics, and Structural Life Science , and Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science, and Technology , Japan, and the Japan Society for the Promotion of Science (KAKENHI Grant No. 26293025 (Y.H.) and No. 25460146 (S.F.)). Publisher Copyright: © 2015 Elsevier Ltd.

PY - 2015/7/3

Y1 - 2015/7/3

N2 - Abstract We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we investigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and synthesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing PPARα agonist, and evaluated their PPARα/δ/γ agonistic activity. We found that diethylsilyl derivative 20 exhibited PPARα/δ agonistic activity, and we also obtained a PPARδ-selective agonist, 32. Our results suggest that incorporation of silyl functionality is a useful option for structural development of biologically active compounds.

AB - Abstract We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we investigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and synthesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing PPARα agonist, and evaluated their PPARα/δ/γ agonistic activity. We found that diethylsilyl derivative 20 exhibited PPARα/δ agonistic activity, and we also obtained a PPARδ-selective agonist, 32. Our results suggest that incorporation of silyl functionality is a useful option for structural development of biologically active compounds.

KW - PPAR

KW - Peroxisome proliferator-activated receptor

KW - Sila-substitution

KW - Silicon

KW - cis-Olefin mimetic

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Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists

Abstract

Keywords

ASJC Scopus subject areas

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