Synthesis and antiapoptotic activity of a novel analogue of the neutral sphingomyelinase inhibitor scyphostatin

The enantioselective synthesis of an analogue of scyphostatin, a potent inhibitor of the neutral sphingomyelinase, is described. The synthesis starts with cyclohexanone and a protected D-serine derivative. The key step is an asymmetric hydroxylation to access a hydroxycyclohexanone, which is transformed into a substituted hydroxycyclohexenone. This is converted into the scyphostatin analogue 14, a chemically and metabolically stabilised compound lacking the epoxy function of the natural congener and carrying a palmitic acid group instead of the native trienoyl residue. An evaluation of the biological activity of 14 revealed neutrol sphingomyelinose inhibition in several in vivo test systems (monocytes, macrophages, hepatocytes) monitoring antiopoptotic effects and the inversion of phorbolester-induced translocation of green fluorescent protein labelled kinase (protein kinose C-alpha).