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

Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Bioorganic & medicinal chemistry (Impact Factor: 2.79). 08/2011; 19(18):5402-8. DOI: 10.1016/j.bmc.2011.07.061
Source: PubMed


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.

9 Reads
  • Source
    • "Moreover, Yahya and co-workers revealed that Jaspine B inhibited sphingomyelin synthase (SMS) and consequently increased intracellular ceramide levels, resulting in apoptosis in tumor cell by a caspase-dependent pathway [3] [4]. Fujii and coworkers revealed that Jaspine B and its diastereoisomers inhibited sphingosine kinases (SphKs) and atypical protein kinase C [5] [6]. Due to its remarkable bioactivities and structural novelty, much more effort has been devoted to the synthesis of Jaspine B, its stereoisomers and analogues [3,5,7e18]. 1, 2, 3-Triazoles, as an important class of heterocycles, display a wide range of biological activities [19e23] and are regarded as the interesting scaffold with significant anticancer profile in many human cell lines [24e27]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Two series of more available novel 1,2,3-triazole-Jaspine B hybrids were efficiently synthesized employing click chemistry approach and evaluated for their cytotoxic activities against three human cancer cell lines (EC-9706, MGC-803 and MCF-7). Among them, compound 14h showed excellent inhibition against MCF-7 (IC50 = 1.93 μM) and was more potent than 5-Fu and Jaspine B against all three cancer cell lines. Further investigation of apoptosis assay and cell cycle analysis demonstrated that compound 14h caused cellular early and late apoptosis and arrested the cell cycle at G2/M phase in a concentration- and time-independent manner. This was the first report about the synthesis and in vitro cytotoxic evaluation of 1,2,3-triazole-Jaspine B hybrids.
    European Journal of Medicinal Chemistry 03/2014; 80C:593-604. DOI:10.1016/j.ejmech.2014.03.022 · 3.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aminohydroxylation of prochiral divinylcarbinol and subsequent Pd(II)-catalysed oxy-/amidocarbonylation of aminopentenediols is reported. The method was applied to the preparation of useful building blocks for syntheses of cytotoxic jaspines and glycosidase inhibitor DLX-homologues. The key intermediates, tetrahydrofuranolactones (l-arabino-II) and pyrrolidinolactones (l-arabino-IX and l-xylo-IX), were prepared in a short 2-step sequence from divinylcarbinol.
    Chemical Papers- Slovak Academy of Sciences 01/2012; 67(1). DOI:10.2478/s11696-012-0224-5 · 1.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A formal synthesis of Jaspine B was completed in 42.4% overall yield with only three purification steps (one by crystallization and two by column chromatography). The key step in the synthesis involves a regio- and stereoselective epoxide ring-opening reaction and the configuration inversion of the C3-hydroxyl group through oxidation and reduction. All of the reagents and materials used were quite common and inexpensive.
    Carbohydrate research 04/2012; 351:126-9. DOI:10.1016/j.carres.2012.01.013 · 1.93 Impact Factor
Show more