Synthesis of highly fluorinated di-O-alk(en)yl-glycerophospholipids and evaluation of their biological tolerance

The syntheses of various fluorocarbon/fluorocarbon and fluorocarbon/hydrocarbon rac-1,2- and 1,3-di-O-alk(en)ylglycerophosphocholines and rac-1,2-di-O-alkylglycerophosphoethanolamines (see Fig. 2), which may be used as components for drug-carrier and delivery systems, are described together with some results concerning their biological tolerance. They were obtained by phosphorylation of perfluoroalkylated rac-di-O-alk(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-benzylglycerol using perfluoroalkylated mesylates, then hydrogenolysis for benzyl deprotection (Scheme 1). The two different hydrophobic chains in the mixed fluorocarbon/ fluorocarbon and fluorocarbon/hydrocarbon 1,2-di-O-alk(en)ylglycerols were introduced starting from 1,2-O-isopropylidene- then O-trityl-protected glycerols or from 1,3-O-benzylidene-glycerol (Schemes 3 and 4). The perfluoroalkylated O-alkenylglycerols were obtained by O-alkylation of a glycerol derivative using an omega-unsaturated alkenyl reagent, the perfluoroalkyl segment being connected onto the double bond in a subsequent step (Schemes 1 and 3). The perfluoroalkylated symmetrical and mixed 1,3-di-O-alkylglycerols were synthesized by displacement of the Cl-atom in epichlorohydrin by perfluoroalkylated alcohols, then catalytic (SnCl4) opening of the oxirane ring of the resulting alkyl glycidyl ethers in neat alcohols (Scheme 5). When injected 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.