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

Research output: Contribution to journalArticle

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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) ≥30μM; IC50 (SphK2)=2.2μM] and the methyl ether derivative 22 [IC50 (SphK1)=4.0μM; IC50 (SphK2) ≥30μM].

Original languageEnglish
JournalBioorganic and Medicinal Chemistry
DOIs
Publication statusAccepted/In press - 2017 Feb 28

Fingerprint

Structure-Activity Relationship
Inhibitory Concentration 50
Derivatives
Methyl Ethers
Atoms
Functional groups
Cross Reactions
Protein Isoforms
Carbon
Oxygen
pachastrissamine
sphingosine kinase

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

Cite this

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, 28.02.2017.

Research output: Contribution to journalArticle

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. 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.
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AU - Iwata, Akira

AU - Otsuki, Kazuhiro

AU - Maruyama, Toru

AU - Nakamura, Shinya

AU - Nakanishi, Isao

AU - Inuki, Shinsuke

AU - Fujii, Nobutaka

AU - Oishi, Shinya

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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) ≥30μM; IC50 (SphK2)=2.2μM] and the methyl ether derivative 22 [IC50 (SphK1)=4.0μM; IC50 (SphK2) ≥30μM].

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