Pachastrissamine (jaspine B) and its stereoisomers inhibit sphingosine kinases and atypical protein kinase C

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...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2011-09, Vol.19 (18), p.5402-5408
Hauptverfasser:	Yoshimitsu, Yuji, Oishi, Shinya, Miyagaki, Jun, Inuki, Shinsuke, Ohno, Hiroaki, Fujii, Nobutaka
Format:	Artikel
Sprache:	eng
Schlagworte:	Antineoplastic agents Biological and medical sciences ceramides Dose-Response Relationship, Drug General aspects in vitro studies Jaspine B Medical sciences Molecular Conformation Pachastrissamine Pharmacology. Drug treatments Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors Phosphotransferases (Alcohol Group Acceptor) - metabolism Protein kinase C Protein Kinase C - antagonists & inhibitors Protein Kinase C - metabolism Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Sphingolipid sphingosine Sphingosine - analogs & derivatives Sphingosine - chemical synthesis Sphingosine - chemistry Sphingosine - pharmacology Sphingosine kinase Stereoisomerism stereoisomers Structure-Activity Relationship
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Zusammenfassung:	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.
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2011.07.061