Total enantioselective synthesis and in vivo biological evaluation of a novel fluorescent BODIPY alpha-galactosylceramide.
Natural killer T (NKT) cells are a distinct subset of mature lymphocytes endowed with features of activated and regulatory T cells. alpha-Galactosylceramides (alpha-GalCers), the synthetic prototype of which is KRN7000, are the only natural reagents recognised by the T-cell receptor of NKT cells. The alpha-GalCer-activated NKT cells promptly release IFN gamma and IL-4 (IFN=interferon; IL=interleukin) and undergo apoptotic death within hours. In mice, activated NKT cells are responsible for antitumour activity and protection against autoimmune diseases. KRN7000 can thus be considered as the root of a family of novel immunoregulatory drugs. To get insights into the in vivo behaviour of alpha-galactosylceramides, an original fluorescent derivative has been prepared by following a convergent synthetic scheme. This strategy allows the introduction of different acyl chains, carbohydrate residues and various labels in the final steps of the synthesis. The fluorescent BODIPY probe derived from a versatile glycolipid precursor is as active as KRN7000 for inducing apoptosis of liver NKT cells. Fluorescence was detected in peritoneal macrophages and splenic antigen-presenting cells, in Kupffer-like cells in the liver, but not in lymphocytes.
Vo-Hoang
Yen
Y
Laboratoire de Chimie Thérapeutique, UMR 8638 associée au CNRS et à l'Université René Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'observatoire, 75270 Paris cedex 06, France.
Micouin
Laurent
L
Ronet
Catherine
C
Gachelin
Gabriel
G
Bonin
Martine
M
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D005434:Flow Cytometry; D005453:Fluorescence; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005699:Galactosylceramides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D006017:Glycolipids / Q000138:chemical synthesis / Q000737:chemistry; D007091:Image Processing, Computer-Assisted; D007202:Indicators and Reagents; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007694:Killer Cells, Natural / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013237:Stereoisomerism
D005456:Fluorescent Dyes; D005699:Galactosylceramides; D006017:Glycolipids; D007202:Indicators and Reagents; C103873:KRN 7000