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 language | English |
|---|---|
| Journal | Bioorganic and Medicinal Chemistry |
| DOIs | |
| Publication status | Accepted/In press - 2017 Feb 28 |
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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 journal › Article
}
TY - JOUR
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
PY - 2017/2/28
Y1 - 2017/2/28
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) ≥30μM; IC50 (SphK2)=2.2μM] and the methyl ether derivative 22 [IC50 (SphK1)=4.0μM; IC50 (SphK2) ≥30μM].
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].
KW - Jaspine B
KW - Kinase inhibitor
KW - Sphingosine kinase
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=85017379147&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017379147&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2017.03.059
DO - 10.1016/j.bmc.2017.03.059
M3 - Article
C2 - 28408190
AN - SCOPUS:85017379147
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
ER -