Synthesis and evaluation of sphingosine analogues as inhibitors of sphingosine kinases

Wong, L., Tan, S. S.L., Lam, Y. and Melendez, A. J. (2009) Synthesis and evaluation of sphingosine analogues as inhibitors of sphingosine kinases. Journal of Medicinal Chemistry, 52(12), pp. 3618-3626. (doi: 10.1021/jm900121d)

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Sphingolipid-metabolizing enzymes control the critical balance of the cellular levels of sphingolipids, including the apoptotic inducing ceramide (Cer) and the proliferative inducing sphingosine 1-phosphate (S1P). The production of S1P, catalyzed by the action of sphingosine kinases (SPHKs), is known to be critical for many cellular processes. However, it is suggested that SPHK, and/or its catalytic product S1P, plays critical roles in various diseases including autoimmune diseases, cancer, and allergies. However, there is a great limitation of specific pharmacological inhibitors for SPHKs. In this paper, we describe a novel and stereoselective method of synthesizing SPHKs inhibitors. We generated a number of novel compounds and identified a number of specific inhibitors of human SPHKs. These compounds demonstrated inhibition of SPHKs at micromolar concentrations, making them more potent than dimethylsphingosine (DMS), a well-known inhibitor of SPHKs. In particular, one of the inhibitors was found to be selective toward a particular isoform of SPHK.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Melendez Romero, Dr Alirio
Authors: Wong, L., Tan, S. S.L., Lam, Y., and Melendez, A. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Medicinal Chemistry
Journal Abbr.:J. Med. Chem.
Publisher:American Chemical Society
ISSN (Online):1520-4804
Published Online:26 May 2009
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
462311Therapeutic potential of Sphingosine Kinase blockage in allergic anaphylaxis.Alirio Melendez RomeroMedical Research Council (MRC)G0700794Institute of Infection Immunity and Inflammation