Journal of Lipid Research, Vol 28, 733-738, Copyright © 1987 by Lipid Research, Inc.
Synthesis and biochemical studies of analogs of platelet-activating factor bearing a methyl group at C2 of the glycerol backbone
R Bittman, NM Witzke, TC Lee, ML Blank and F Snyder
Two platelet-activating factor (PAF) analogs containing a methyl group at
C2 of the glycerol moiety were synthesized, and some of their biochemical
properties were investigated. 1-O-Hexadecyl-2-C,O-dimethyl-
rac-glycero-3-phosphocholine (2-methyl-2-methoxy PAF) was prepared in a
synthetic scheme beginning with the etherification of 2-methylpropen-1- ol.
A reaction sequence involving hydroxylation, tritylation, alkylation, and
detritylation afforded 1-O-hexadecyl-2-C,O-dimethyl-rac- glycerol, which
was converted into the phosphocholine. A 2-lyso derivative of this PAF
analog (2-methyl-lyso PAF) was synthesized from
1-O-hexadecyl-2-C-methyl-3-O-trityl-rac-glycerol. Benzylation followed by
detritylation gave 1-O-hexadecyl-2-C-methyl-2-O-benzyl-rac-glycerol, which
was converted into the phosphocholine compound. Hydrogenolysis afforded
1-O-hexadecyl-2-C-methyl-rac-glycero-3-phospholine (2-methyl- lyso PAF).
The 2-methyl-lyso PAF analog served as a substrate for the
acetyl-CoA-dependent acetyltransferase that acetylates 1-O-alkyl-2-lyso-
sn-glycero-3-phosphocholine. However, 2-methyl-lyso PAF did not have a
significant effect on the activities of a CoA-independent transacylase or
of the acetylhydrolase that inactivates PAF, and thus does not appear to be
a substrate or an inhibitor, respectively, for these enzymes. In addition,
this analog exhibited only one-half of the antitumor activity of
rac-1-O-alkyl-2-methoxy-rac-glycero-3- phosphocholine in human leukemic
(HL-60) cells, and elicited no hypotensive response in rats and no
platelet-activating activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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