SYNTHESIS OF HIGHLY FLUORINATED DI-O-ALK(EN)YL-GLYCEROPHOSPHOLIPIDS AND EVALUATION OF THEIR BIOLOGICAL TOLERANCE

The syntheses of various fluorocarbon/fluorocarbon and fluorocarbon/hy drocarbon rac-1,2- and 1,3-di-O-alk(en)ylglycerophosphocholines and ra c-1,2-di-O-alkylglycerophosphoethanolamines (see Fig. 2), which may be used as components for drug-carrier and delivery systems, are describ ed together with some results concerning their biological tolerance. T hey were obtained by phosphorylation of perfluoroalkylated rac-di-O-al k(en)ylglycerols using POCl3, then condensation with choline tosylate or N-Boc-ethanolamine (2-[(tert-butoxy)carbonylamino]ethanol) followed by Boc-deprotection (Schemes 6-8). The fluorocarbon/fluorocarbon 1,2- di-O-alkylglycerols were prepared by O-alkylation of rac-1-O-benzylgly cerol using perfluoroalkylated mesylates, then hydrogenolysis for benz yl deprotection (Scheme 1). The two different hydrophobic chains in th e mixed fluorocarbon/ fluorocarbon and fluorocarbon/hydrocarbon 1,2-di -O-alk(en)ylglycerols were introduced starting from 1,2-O-isopropylide ne- then O-trityl-protected glycerols or from 1,3-O-benzylidene-glycer ol (Schemes 3 and 4). The perfluoroalkylated O-alkenylglycerols were o btained by O-alkylation of a glycerol derivative using an omega-unsatu rated alkenyl reagent, the perfluoroalkyl segment being connected onto the double bond in a subsequent step (Schemes 1 and 3). The perfluoro alkylated symmetrical and mixed 1,3-di-O-alkylglycerols were synthesiz ed by displacement of the Cl-atom in epichlorohydrin by perfluoroalkyl ated alcohols, then catalytic (SnCl4) opening of the oxirane ring of t he resulting alkyl glycidyl ethers in neat alcohols (Scheme 5). When i njected intravenously into mice, acute maximum tolerated doses higher than 1500 and 2000 mg/kg body weight were observed for the fluorinated glycerophosphocholines, indicating a very promising in vivo tolerance .