Synthesis and biochemical investigation of scyphostatin analogues as inhibitors of neutral sphingomyelinase

The sphingolipid ceramide is considered to be an important intracellular mediator. However, many aspects of its action and the role of several different ceramide generating sphingomyelinases are still unclear. Recently, we reported on the synthesis of the first selective irreversible inhibitor of the neutral sphingomyelinase (N-SMase), as well as the identification of Manumycin A and some of its analogues as irreversible inhibitors of N-SMase. For the development of pharmacologically interesting competitive inhibitors of N-SMase, structure-activity studies are essential. Herein we show the synthesis and enzymatic investigation of two scyphostatin analogues 3a and 3b, revealing the importance of the primary hydroxy group in compound 2 for N-SMase inhibition.