Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure–activity relationship study of 4-epi-jaspine B

Hiroaki Ohno; Maho Honda; Naoka Hamada; Jun Miyagaki; Akira Iwata; Kazuhiro Otsuki; Toru Maruyama; Shinya Nakamura; Isao Nakanishi; Shinsuke Inuki; Nobutaka Fujii; Shinya Oishi

doi:10.1016/j.bmc.2017.03.059

Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure–activity relationship study of 4-epi-jaspine B

Hiroaki Ohno, Maho Honda, Naoka Hamada, Jun Miyagaki, Akira Iwata, Kazuhiro Otsuki, Toru Maruyama, Shinya Nakamura, Isao Nakanishi, Shinsuke Inuki, Nobutaka Fujii, Shinya Oishi

Department of Chemistry

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

6 Citations (Scopus)

Abstract

We recently reported that 4-epi-jaspine B exhibits potent inhibitory activity towards sphingosine kinases (SphKs). In this study, we investigated the effects of modifying the 2-alkyl group, as well as the functional groups on the THF ring of 4-epi-jaspine B using a diversity-oriented synthesis approach based on a late-stage cross metathesis reaction. The introduction of a p-phenylene tether to the alkyl group was favored in most cases, whereas the replacement of a carbon atom with an oxygen atom led to a decrease in the inhibitory activity. Furthermore, the introduction of a bulky alkyl group at the terminus led to a slight increase in the inhibitory activity of this series towards SphKs compared with 4-epi-jaspine B (the Q values of compound 13 for SphK1 and SphK2 were 0.2 and 0.4, respectively). Based on this study, we identified two isoform selective inhibitors, including the m-phenylene derivative 4 [IC₅₀ (SphK1) ≥30 μM; IC₅₀ (SphK2) = 2.2 μM] and the methyl ether derivative 22 [IC₅₀ (SphK1) = 4.0 μM; IC₅₀ (SphK2) ≥30 μM].

Original language	English
Pages (from-to)	3046-3052
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	25
Issue number	12
DOIs	https://doi.org/10.1016/j.bmc.2017.03.059
Publication status	Published - 2017

Keywords

Jaspine B
Kinase inhibitor
Sphingosine kinase
Structure–activity relationship

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.2017.03.059

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Ohno, H., Honda, M., Hamada, N., Miyagaki, J., Iwata, A., Otsuki, K., Maruyama, T., Nakamura, S., Nakanishi, I., Inuki, S., Fujii, N., & Oishi, S. (2017). Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure–activity relationship study of 4-epi-jaspine B. Bioorganic and Medicinal Chemistry, 25(12), 3046-3052. https://doi.org/10.1016/j.bmc.2017.03.059

Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure–activity relationship study of 4-epi-jaspine B. / Ohno, Hiroaki; Honda, Maho; Hamada, Naoka; Miyagaki, Jun; Iwata, Akira; Otsuki, Kazuhiro; Maruyama, Toru; Nakamura, Shinya; Nakanishi, Isao; Inuki, Shinsuke; Fujii, Nobutaka; Oishi, Shinya.

In: Bioorganic and Medicinal Chemistry, Vol. 25, No. 12, 2017, p. 3046-3052.

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

Ohno, H, Honda, M, Hamada, N, Miyagaki, J, Iwata, A, Otsuki, K, Maruyama, T, Nakamura, S, Nakanishi, I, Inuki, S, Fujii, N & Oishi, S 2017, 'Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure–activity relationship study of 4-epi-jaspine B', Bioorganic and Medicinal Chemistry, vol. 25, no. 12, pp. 3046-3052. https://doi.org/10.1016/j.bmc.2017.03.059

Ohno, Hiroaki ; Honda, Maho ; Hamada, Naoka ; Miyagaki, Jun ; Iwata, Akira ; Otsuki, Kazuhiro ; Maruyama, Toru ; Nakamura, Shinya ; Nakanishi, Isao ; Inuki, Shinsuke ; Fujii, Nobutaka ; Oishi, Shinya. / Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure–activity relationship study of 4-epi-jaspine B. In: Bioorganic and Medicinal Chemistry. 2017 ; Vol. 25, No. 12. pp. 3046-3052.

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title = "Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure–activity relationship study of 4-epi-jaspine B",

abstract = "We recently reported that 4-epi-jaspine B exhibits potent inhibitory activity towards sphingosine kinases (SphKs). In this study, we investigated the effects of modifying the 2-alkyl group, as well as the functional groups on the THF ring of 4-epi-jaspine B using a diversity-oriented synthesis approach based on a late-stage cross metathesis reaction. The introduction of a p-phenylene tether to the alkyl group was favored in most cases, whereas the replacement of a carbon atom with an oxygen atom led to a decrease in the inhibitory activity. Furthermore, the introduction of a bulky alkyl group at the terminus led to a slight increase in the inhibitory activity of this series towards SphKs compared with 4-epi-jaspine B (the Q values of compound 13 for SphK1 and SphK2 were 0.2 and 0.4, respectively). Based on this study, we identified two isoform selective inhibitors, including the m-phenylene derivative 4 [IC50 (SphK1) ≥30 μM; IC50 (SphK2) = 2.2 μM] and the methyl ether derivative 22 [IC50 (SphK1) = 4.0 μM; IC50 (SphK2) ≥30 μM].",

keywords = "Jaspine B, Kinase inhibitor, Sphingosine kinase, Structure–activity relationship",

author = "Hiroaki Ohno and Maho Honda and Naoka Hamada and Jun Miyagaki and Akira Iwata and Kazuhiro Otsuki and Toru Maruyama and Shinya Nakamura and Isao Nakanishi and Shinsuke Inuki and Nobutaka Fujii and Shinya Oishi",

note = "Funding Information: This work was supported by the JSPS KAKENHI (Grant Numbers JP15KT0061 and JP15H04654), the Uehara Memorial Foundation, Japan, and the Platform for Drug Design, Discovery and Development from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",

year = "2017",

doi = "10.1016/j.bmc.2017.03.059",

language = "English",

volume = "25",

pages = "3046--3052",

journal = "Bioorganic and Medicinal Chemistry",

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T1 - Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure–activity relationship study of 4-epi-jaspine B

AU - Ohno, Hiroaki

AU - Honda, Maho

AU - Hamada, Naoka

AU - Miyagaki, Jun

AU - Iwata, Akira

AU - Otsuki, Kazuhiro

AU - Maruyama, Toru

AU - Nakamura, Shinya

AU - Nakanishi, Isao

AU - Inuki, Shinsuke

AU - Fujii, Nobutaka

AU - Oishi, Shinya

N1 - Funding Information: This work was supported by the JSPS KAKENHI (Grant Numbers JP15KT0061 and JP15H04654), the Uehara Memorial Foundation, Japan, and the Platform for Drug Design, Discovery and Development from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. Publisher Copyright: © 2017 Elsevier Ltd

PY - 2017

Y1 - 2017

N2 - We recently reported that 4-epi-jaspine B exhibits potent inhibitory activity towards sphingosine kinases (SphKs). In this study, we investigated the effects of modifying the 2-alkyl group, as well as the functional groups on the THF ring of 4-epi-jaspine B using a diversity-oriented synthesis approach based on a late-stage cross metathesis reaction. The introduction of a p-phenylene tether to the alkyl group was favored in most cases, whereas the replacement of a carbon atom with an oxygen atom led to a decrease in the inhibitory activity. Furthermore, the introduction of a bulky alkyl group at the terminus led to a slight increase in the inhibitory activity of this series towards SphKs compared with 4-epi-jaspine B (the Q values of compound 13 for SphK1 and SphK2 were 0.2 and 0.4, respectively). Based on this study, we identified two isoform selective inhibitors, including the m-phenylene derivative 4 [IC50 (SphK1) ≥30 μM; IC50 (SphK2) = 2.2 μM] and the methyl ether derivative 22 [IC50 (SphK1) = 4.0 μM; IC50 (SphK2) ≥30 μM].

AB - We recently reported that 4-epi-jaspine B exhibits potent inhibitory activity towards sphingosine kinases (SphKs). In this study, we investigated the effects of modifying the 2-alkyl group, as well as the functional groups on the THF ring of 4-epi-jaspine B using a diversity-oriented synthesis approach based on a late-stage cross metathesis reaction. The introduction of a p-phenylene tether to the alkyl group was favored in most cases, whereas the replacement of a carbon atom with an oxygen atom led to a decrease in the inhibitory activity. Furthermore, the introduction of a bulky alkyl group at the terminus led to a slight increase in the inhibitory activity of this series towards SphKs compared with 4-epi-jaspine B (the Q values of compound 13 for SphK1 and SphK2 were 0.2 and 0.4, respectively). Based on this study, we identified two isoform selective inhibitors, including the m-phenylene derivative 4 [IC50 (SphK1) ≥30 μM; IC50 (SphK2) = 2.2 μM] and the methyl ether derivative 22 [IC50 (SphK1) = 4.0 μM; IC50 (SphK2) ≥30 μM].

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KW - Kinase inhibitor

KW - Sphingosine kinase

KW - Structure–activity relationship

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JF - Bioorganic and Medicinal Chemistry

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IS - 12

ER -

Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure–activity relationship study of 4-epi-jaspine B

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