S. Gaentzler et P. Vierling, PERFLUOROALKYLATED PHOSPHOCHOLINES - IMPROVED SYNTHESIS, SURFACE-ACTIVITY, FLUOROCARBON EMULSIFYING CAPABILITY AND BIOLOGICAL PROPERTIES, New journal of chemistry, 17(5), 1993, pp. 337-344
A series of new perfluoroalkylated phosphocholines (F-alkyl-PC) 1 to 3
and the N-ethyl phosphocholine 4 have been synthesized in 55-75% yiel
ds through a simpler and more convenient process than their previously
synthesized homologues 5 and 6 (direct phosphorylation of the F-alkyl
ated alcohol by phosphorus oxytrichloride, subsequent condensation wit
h the choline tosylates). Compounds 1 to 6 all exhibit strong surface
activity, the most efficient and most effective is F8C5PC, 3. The F-al
kyl-PCs display much lower critical micellar concentration (cmc) value
s than their hydrocarbon analogs. The relative weight of the Fn tail i
n the hydrophobic chain and/or the Fn tail length play a significant p
art in the value of the cmc's. When compared to natural EYP (egg yolk
phospholipids), F-alkyl-PCs exhibit significantly better fluorocarbon
emulsion-stabilizing properties, which increase with raising the relat
ive weight of the Fn tail. 50% w/v concentrated F-decalin emulsions fo
rmulated with F-alkyl-PCs were stable for over 1 year at 40-degrees-C
while phase separation was observed in the EYP-based emulsions. Furthe
rmore, the F-decalin emulsions prepared with the most efficient compou
nds, i.e. F8C2PC (5) and F8C5PC (3), have, under similar aging conditi
ons, significantly smaller particle sizes. The F-alkyl-PCs 1 to 5 show
no detectable hemolytic activity even at concentrations as high as 15
to 25 g/L. The F8C5 fluorophilic/hydrophobic chain appears to be an o
ptimal compromise in terms of high surface activities, efficient fluor
ocarbon emulsifying properties and biological tolerance. However, the
acute in vivo toxicity of these compounds when administered intravenou
sly, with LD50 i.v. values in the 25-300 mg/kg body weight range in mi
ce, is considered to preclude their use in injectable fluorocarbon emu
lsions because of the unusually large doses needed to be administered
to patients in oxygen-delivery applications. The presence of a trans d
ouble bond between the Fn tail and the hydrocarbon spacer seems to hav
e a slight destabilizing effect on fluorocarbon emulsions. A NMe2Et gr
oup in the polar head induces a more significant decrease of fluorocar
bon emulsion stability, which is not compensated by an increase in in
vivo tolerance.