Pachastrissamine (jaspine B) and its stereoisomers inhibit sphingosine kinases and atypical protein kinase C

Yuji Yoshimitsu; Shinya Oishi; Jun Miyagaki; Shinsuke Inuki; Hiroaki Ohno; Nobutaka Fujii

doi:10.1016/j.bmc.2011.07.061

Pachastrissamine (jaspine B) and its stereoisomers inhibit sphingosine kinases and atypical protein kinase C

Yuji Yoshimitsu, Shinya Oishi, Jun Miyagaki, Shinsuke Inuki, Hiroaki Ohno, Nobutaka Fujii

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

54 Citations (Scopus)

Abstract

Sphingosine kinases (SphKs) are oncogenic enzymes that regulate the critical balance between ceramide and sphingosine-1-phosphate. Much effort has been dedicated to develop inhibitors against these enzymes. Naturally occurring pachastrissamine (jaspine B) and all its stereoisomers were prepared and evaluated for their inhibitory effects against SphKs. All eight stereoisomers exhibited moderate to potent inhibitory activity against SphK1 and SphK2. Inhibitory effects were profiled against protein kinase C (PKC) isoforms by in vitro experiments. Atypical PKCs (PKCζ and PKCι) were inhibited by several pachastrissamine stereoisomers. The improved activity over N,N-dimethylsphingosine suggests that the cyclic scaffold in pachastrissamines facilitates potential favorable interactions with SphKs and PKCs.

Original language	English
Pages (from-to)	5402-5408
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	19
Issue number	18
DOIs	https://doi.org/10.1016/j.bmc.2011.07.061
Publication status	Published - 2011 Sept 15
Externally published	Yes

Keywords

Jaspine B
Pachastrissamine
Protein kinase C
Sphingolipid
Sphingosine kinase

ASJC Scopus subject areas

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

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10.1016/j.bmc.2011.07.061

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title = "Pachastrissamine (jaspine B) and its stereoisomers inhibit sphingosine kinases and atypical protein kinase C",

abstract = "Sphingosine kinases (SphKs) are oncogenic enzymes that regulate the critical balance between ceramide and sphingosine-1-phosphate. Much effort has been dedicated to develop inhibitors against these enzymes. Naturally occurring pachastrissamine (jaspine B) and all its stereoisomers were prepared and evaluated for their inhibitory effects against SphKs. All eight stereoisomers exhibited moderate to potent inhibitory activity against SphK1 and SphK2. Inhibitory effects were profiled against protein kinase C (PKC) isoforms by in vitro experiments. Atypical PKCs (PKCζ and PKCι) were inhibited by several pachastrissamine stereoisomers. The improved activity over N,N-dimethylsphingosine suggests that the cyclic scaffold in pachastrissamines facilitates potential favorable interactions with SphKs and PKCs.",

keywords = "Jaspine B, Pachastrissamine, Protein kinase C, Sphingolipid, Sphingosine kinase",

author = "Yuji Yoshimitsu and Shinya Oishi and Jun Miyagaki and Shinsuke Inuki and Hiroaki Ohno and Nobutaka Fujii",

note = "Funding Information: This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Targeted Proteins Research Program. Y.Y. and S.I. are grateful for Research Fellowships from the Japan Society for the Promotion of Science (JSPS) for Young Scientists. ",

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AU - Yoshimitsu, Yuji

AU - Oishi, Shinya

AU - Miyagaki, Jun

AU - Inuki, Shinsuke

AU - Ohno, Hiroaki

AU - Fujii, Nobutaka

N1 - Funding Information: This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Targeted Proteins Research Program. Y.Y. and S.I. are grateful for Research Fellowships from the Japan Society for the Promotion of Science (JSPS) for Young Scientists.

PY - 2011/9/15

Y1 - 2011/9/15

N2 - Sphingosine kinases (SphKs) are oncogenic enzymes that regulate the critical balance between ceramide and sphingosine-1-phosphate. Much effort has been dedicated to develop inhibitors against these enzymes. Naturally occurring pachastrissamine (jaspine B) and all its stereoisomers were prepared and evaluated for their inhibitory effects against SphKs. All eight stereoisomers exhibited moderate to potent inhibitory activity against SphK1 and SphK2. Inhibitory effects were profiled against protein kinase C (PKC) isoforms by in vitro experiments. Atypical PKCs (PKCζ and PKCι) were inhibited by several pachastrissamine stereoisomers. The improved activity over N,N-dimethylsphingosine suggests that the cyclic scaffold in pachastrissamines facilitates potential favorable interactions with SphKs and PKCs.

AB - Sphingosine kinases (SphKs) are oncogenic enzymes that regulate the critical balance between ceramide and sphingosine-1-phosphate. Much effort has been dedicated to develop inhibitors against these enzymes. Naturally occurring pachastrissamine (jaspine B) and all its stereoisomers were prepared and evaluated for their inhibitory effects against SphKs. All eight stereoisomers exhibited moderate to potent inhibitory activity against SphK1 and SphK2. Inhibitory effects were profiled against protein kinase C (PKC) isoforms by in vitro experiments. Atypical PKCs (PKCζ and PKCι) were inhibited by several pachastrissamine stereoisomers. The improved activity over N,N-dimethylsphingosine suggests that the cyclic scaffold in pachastrissamines facilitates potential favorable interactions with SphKs and PKCs.

KW - Jaspine B

KW - Pachastrissamine

KW - Protein kinase C

KW - Sphingolipid

KW - Sphingosine kinase

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Pachastrissamine (jaspine B) and its stereoisomers inhibit sphingosine kinases and atypical protein kinase C

Abstract

Keywords

ASJC Scopus subject areas

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