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 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-alpha).
Claus
Ralf A
RA
Department for Anaesthesiology and Intensive Care Therapy, Division for Experimental Anaesthesiology, Friedrich-Schiller-University Jena, Research Centre Lobeda, Erlanger Allee 101, 07747 Jena, Germany.
Wüstholz
Annette
A
Müller
Stefan
S
Bockmeyer
Clemens L
CL
Riedel
Norman H
NH
Kinscherf
Ralf
R
Deigner
Hans-Peter
HP
D000577:Amides / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011753:Pyrones / Q000737:chemistry*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000577:Amides; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D011753:Pyrones; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; C121123:scyphostatin; D011065:Poly(ADP-ribose) Polymerases; D011493:Protein Kinase C; D013108:Sphingomyelin Phosphodiesterase