Issue 10, 2013
From the journal:

MedChemComm

Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells†

Hoe-Sup Byun,a   Susan Pyne,b   Neil MacRitchie,b   Nigel J. Pyneb  and  Robert Bittman*a  

* Corresponding authors

a Department of Chemistry and Biochemistry, Queens College, The City University of New York, Flushing, NY 11367-1597, USA
E-mail: robert.bittman@qc.cuny.edu
Tel: +1 718-997-3279

b Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK

Abstract

Sphingosine 1-phosphate (S1P) is involved in hyper-proliferative diseases such as cancer and pulmonary arterial hypertension. We have synthesized inhibitors that are selective for the two isoforms of sphingosine kinase (SK1 and SK2) that catalyze the synthesis of S1P. A thiourea adduct of sphinganine (F02) is selective for SK2 whereas the 1-deoxysphinganines 55-21 and 77-7 are selective for SK1. (2S,3R)-1-Deoxysphinganine (55-21) induced the proteasomal degradation of SK1 in human pulmonary arterial smooth muscle cells and inhibited DNA synthesis, while the more potent SK1 inhibitors PF-543 and VPC96091 failed to inhibit DNA synthesis. These findings indicate that moderate potency inhibitors such as 55-21 are likely to have utility in unraveling the functions of SK1 in inflammatory and hyperproliferative disorders.

Graphical abstract: Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells

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Article information

DOI
https://doi.org/10.1039/C3MD00201B
Article type
Concise Article
Submitted
16 Jul 2013
Accepted
05 Aug 2013
First published
06 Aug 2013
This article is Open Access
Creative Commons BY license

Med. Chem. Commun., 2013,4, 1394-1399

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Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells

H. Byun, S. Pyne, N. MacRitchie, N. J. Pyne and R. Bittman, Med. Chem. Commun., 2013, 4, 1394 DOI: 10.1039/C3MD00201B

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