Synthesis and Evaluation of Sphingosine Analogues as Inhibitors of Sphingosine Kinases

Abstract

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.