Synthesis and structure of phosphatidylinositol dimannoside.
(R)-tuberculostearic acid (2) was synthesized in seven steps from (S)-citronellol (5). The carbon chain of 2 was assembled by copper-catalyzed cross coupling of (S)-citronellol tosylate (6) and hexylmagnesium bromide; subsequent ozonolysis and reaction with 6-benzyloxyhexylmagnesium bromide furnished alcohol 10. Functional group manipulation afforded (R)-2 in 49% overall yield from 5. DCC coupling of (R)-2 with 3-O-benzyl-1-O-palmitoyl-sn-glycerol (16), followed by hydrogenolytic removal of the benzyl group and treatment with benzyl bis(diisopropyl)phosphoramidite, afforded phosphoramidite 20. Tetrazole-mediated coupling of 20 with PIM1 head group 21 gave 22, and subsequent debenzylation afforded phosphatidylinositol mono-mannoside, PIM1 (23). Similarly, coupling of 20 and 24 and removal of the benzyl protecting groups gave PIM2 (1c). Both 23 and 1c have a clearly defined acylation pattern, which was confirmed by mass spectrometry, with sn-1 palmitoyl and sn-2 tuberculostearoyl groups on the glycerol moiety. Both 23 and 1c were shown to modulate the release of the pro-inflammatory cytokine, IL-12, in a dendritic cell assay.
Dyer
Blake S
BS
University of Otago, P.O. Box 56, Dunedin, New Zealand.
Jones
Jeremy D
JD
Ainge
Gary D
GD
Denis
Michel
M
Larsen
David S
DS
Painter
Gavin F
GF
D000080462:Acyclic Monoterpenes; D000215:Acylation; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002625:Chemistry, Organic / Q000379:methods*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D039821:Monoterpenes / Q000737:chemistry; D010716:Phosphatidylinositols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013229:Stearic Acids / Q000737:chemistry
D000080462:Acyclic Monoterpenes; D016207:Cytokines; D007155:Immunologic Factors; D039821:Monoterpenes; D010716:Phosphatidylinositols; D013229:Stearic Acids; C054977:phosphatidylinositol dimannoside; D018664:Interleukin-12; C026082:tuberculostearic acid; C007078:citronellol