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1.
Bioorg Med Chem ; 25(12): 3046-3052, 2017 06 15.
Article in English | MEDLINE | ID: mdl-28408190

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].


Subject(s)
Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Sphingosine/analogs & derivatives , Humans , Molecular Docking Simulation , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Sphingosine/chemistry , Sphingosine/pharmacology , Structure-Activity Relationship
2.
Bioorg Med Chem ; 19(18): 5402-8, 2011 Sep 15.
Article in English | MEDLINE | ID: mdl-21868240

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.


Subject(s)
Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Sphingosine/analogs & derivatives , Dose-Response Relationship, Drug , Molecular Conformation , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Protein Kinase C/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Sphingosine/chemical synthesis , Sphingosine/chemistry , Sphingosine/pharmacology , Stereoisomerism , Structure-Activity Relationship
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