Potent inhibition of acid sphingomyelinase by phosphoinositide analogues.
The different mammalian sphingomyelinases are involved in cell regulation, apoptosis and inflammatory events. Recent reports suggest pharmacological potential especially for inhibitors of the acid sphingomyelinase. Phosphatidyl inositol-3,5bisphosphate (PtdIns3,5P(2)) is the most potent selective acid sphingomyelinase inhibitor known to date. In the present study, we synthesized analogues of PtdIns3,5P(2) for initial structure-activity-relationship (SAR) studies. We identified an inhibitor that is easy to synthesize, that has superior chemical and biophysical properties when compared to PtdIns3,5P(2) and that should be stable against virtually all phospholipases. Last but not least, the new inhibitor partially protected cells from dexamethasone-induced cell death.
Roth
Anke Gundula
AG
Institut für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Strasse 2, 12489 Berlin, Germany.
Redmer
Susanne
S
Arenz
Christoph
C
D017209:Apoptosis; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D010716:Phosphatidylinositols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D010716:Phosphatidylinositols; D003907:Dexamethasone; D013108:Sphingomyelin Phosphodiesterase