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Synthesis and Antiapoptotic Activity of a Novel Analogue of the Neutral Sphingomyelinase Inhibitor Scyphostatin
Author(s) -
Claus Ralf A.,
Wüstholz Annette,
Müller Stefan,
Bockmeyer Clemens L.,
Riedel Norman H.,
Kinscherf Ralf,
Deigner HansPeter
Publication year - 2005
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200400228
Subject(s) - stereochemistry , chemistry , sphingomyelin , hydroxylation , biochemistry , threonine , serine , in vivo , enzyme , biology , microbiology and biotechnology , membrane
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 neutral sphingomyelinase inhibition in several in vivo test systems (monocytes, macrophages, hepatocytes) monitoring antiapoptotic effects and the inversion of phorbolester‐induced translocation of green fluorescent protein labelled kinase (protein kinase C‐α).