Synthesis and evaluation of sphingosine analogues as inhibitors of sphingosine kinases.
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.
Wong
Lingkai
L
Department of Chemistry, Faculty of Science, National University of Singapore, 3 Science Drive 3, 117543, Singapore.
Tan
Sheryl S L
SS
Lam
Yulin
Y
Melendez
Alirio J
AJ
D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018922:HL-60 Cells; D006801:Humans; D008968:Molecular Conformation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives*; D013237:Stereoisomerism; D000099157:Sphingosine Kinase
D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D013110:Sphingosine; D000099157:Sphingosine Kinase