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

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Ohno H,Honda M,Hamada N,Miyagaki J,Iwata A,Otsuki K,Maruyama T,Nakamura S,Nakanishi I,Inuki S,Fujii N,Oishi S

doi

10.1016/j.bmc.2017.03.059

subject

Has Abstract

pub_date

2017-06-15 00:00:00

pages

3046-3052

issue

12

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(17)30410-8

journal_volume

25

pub_type

杂志文章

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