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A lipid analogue that inhibits sphingomyelin hydrolysis and synthesis, increases ceramide, and leads to cell death.

Abstract
We report the synthesis and characterization of a novel thiourea derivative of sphingomyelin (AD2765). In vitro assays using pure enzyme and/or cell extracts revealed that this compound inhibited the hydrolysis of BODIPY-conjugated or 14C-labeled sphingomyelin by acid sphingomyelinase and Mg2+-dependent neutral sphingomyelinase. Studies in normal human skin fibroblasts further revealed that AD2765 was taken up by cells and inhibited the hydrolysis of BODIPY-conjugated sphingomyelin in situ. In situ and in vitro studies also showed that this compound inhibited the synthesis of sphingomyelin from BODIPY-conjugated ceramide. The specificity of AD2765 for enzymes involved in sphingomyelin metabolism was demonstrated by the fact that it had no effect on the hydrolysis of BODIPY-conjugated ceramide by acid ceramidase or on the synthesis of BODIPY-conjugated glucosylceramide from BODIPY-conjugated ceramide. The overall effect of AD2765 on sphingomyelin metabolism was concentration-dependent, and treatment of normal human skin fibroblasts or cancer cells with this compound at concentrations > 10 microM led to an increase in cellular ceramide and cell death. Thus, AD2765 might be used to manipulate sphingomyelin metabolism in various ways, potentially to reduce substrate accumulation in cells from types A and B Niemann-Pick disease patients, and/or to affect the growth of human cancer cells.
AuthorsPeter I Darroch, Arie Dagan, Tami Granot, Xingxuan He, Shimon Gatt, Edward H Schuchman
JournalJournal of lipid research (J Lipid Res) Vol. 46 Issue 11 Pg. 2315-24 (Nov 2005) ISSN: 0022-2275 [Print] United States
PMID16150832 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene
  • AD2765
  • Boron Compounds
  • Ceramides
  • Lipids
  • Lysosomal-Associated Membrane Protein 2
  • Phosphatidylcholines
  • Sphingomyelins
  • Sphingomyelin Phosphodiesterase
  • 1,2-oleoylphosphatidylcholine
  • Trypan Blue
Topics
  • Boron Compounds (pharmacology)
  • Cell Death
  • Cell Line
  • Cell Line, Tumor
  • Ceramides (chemistry, metabolism)
  • Fibroblasts (metabolism)
  • HL-60 Cells
  • Humans
  • Hydrolysis
  • Jurkat Cells
  • Lipids (chemistry)
  • Lysosomal-Associated Membrane Protein 2 (metabolism)
  • Microscopy, Fluorescence
  • Models, Chemical
  • Niemann-Pick Diseases (metabolism)
  • Phosphatidylcholines (chemistry)
  • Skin (metabolism)
  • Sphingomyelin Phosphodiesterase (metabolism)
  • Sphingomyelins (antagonists & inhibitors, biosynthesis, chemistry, metabolism, pharmacology)
  • Trypan Blue (pharmacology)

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