Rapid identification of immunostimulatory alpha-galactosylceramides using synthetic combinatorial libraries.
Two 60+-membered libraries of alpha-galactosylceramides have been prepared by reactions between activated ester resins and two core, fully deprotected galactosylated sphingoid bases. The libraries were evaluated for their ability to stimulate CD1d-restricted NKT cells, using in vitro stimulation of a murine NKT cell hybridoma line and for their ability to induce the expansion of NKT cells from peripheral blood mononuclear cells (PBMC) of a normal human subject. Our results showed that many compounds constructed on a C18-phytosphingosine base had significant stimulatory activity in both assays. Because no product purification was required, this approach is particularly attractive as a method for rapid synthesis of large libraries of potential immunomodulatory glycosylceramides.
Li
Qian
Q
Department of Chemistry, New York University, New York, New York 10003, USA.
Ndonye
Rachel M
RM
Illarionov
Petr A
PA
Yu
Karl O A
KO
Jerud
Elliot S
ES
Diaz
Kristine
K
Bricard
Gabriel
G
Porcelli
Steven A
SA
Besra
Gurdyal S
GS
Chang
Young-Tae
YT
Howell
Amy R
AR
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D005690:Galactose / Q000737:chemistry; D005699:Galactosylceramides / Q000138:chemical synthesis / Q000276:immunology* / Q000494:pharmacology*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008956:Models, Chemical; D012117:Resins, Synthetic / Q000737:chemistry; D013107:Sphingolipids / Q000737:chemistry; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
D005699:Galactosylceramides; D012117:Resins, Synthetic; D013107:Sphingolipids; C493154:alpha-galactosylceramide; C012491:phytosphingosine; D013110:Sphingosine; D005690:Galactose