Neutral sphingomyelinase as a target for drug design.

The sphingolipid ceramide is an important second messenger assumed to be involved in fundamental processes, including proliferation, differentiation and growth arrest, as well as the induction of apoptosis. Ceramide is generated in a ubiquitous and evolutionarily conserved signaling pathway called the sphingomyelin pathway, through the action of distinct isoforms of sphingomyelinases. An improved understanding of sphingomyelinase-dependent signaling may offer significant insights into the regulation of physiological and pathological processes and may finally provide novel strategies and new targets for pharmacological intervention (e.g., in inflammatory responses, neurodegenerative diseases and cancer). This article summarizes the current knowledge of the role of neutral sphingomyelinase (N-SMase) in cell signaling pathways, and its potential meaning, and demonstrates the opportunity of a specific inhibition of N-SMases as a novel therapeutic target.

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.