Cationic Trialkylphosphates: Synthesis and Transfection Efficacies Compared to Phosphoramidate Analogues

Abstract

International audienceWe report herein the synthesis of a novel family of cationic lipids, characterized by a trimethylammonium headgroup linked through a phosphate function to either two identical or two different lipid chains. The novelty of this study arises from the use of a trialkyl phosphate group to associate the hydrophobic domain to the cationic polar head. The structure of these new cationic lipids, which differs from that of previously reported lipophosphoramidates, is closer to the phospholipids encountered in the plasma membrane, and possesses a phosphocholine polar head. Evaluation of the transfection activity allowed us to compare the efficacy of cationic lipophosphates with that of lipophosphoramidates. These results demonstrate that cationic lipophosphates and lipophosphoramidates having otherwise identical chemical structures exhibit similar transfection efficacies. The second conclusion is that the structure of the lipid domain is a much more important parameter in governing transfection efficacy than the composition of the linker moiety. The best results were obtained with cationic lipophosphates or lipophosphoramidates possessing two different lipid chains, for example one oleyl chain with one phytanyl chain. These nonsymmetric cationic lipids exhibited transfection efficacies that were 10- to 200-fold better than those obtained with Lipofectamine used as a commercial standard

Lipid‐Based Quaternary Ammonium Sophorolipid Amphiphiles with Antimicrobial and Transfection Activities

“…Transfection efficiency : The in vitro reporter gene assay by luciferase measurement was carried out as reported previously . Data were expressed as relative light units (RLU) per milligram of total proteins (means ± SD with n =3).…”

Diastereoselective multicomponent phosphoramidate-aldehyde-dienophile (PAD) process for the synthesis of polysubstituted cyclohex-2-enyl-amine derivatives

“…31 P NMR 𝛿: 6.09 ppm. MS (EI) m/z: 392 (M + , 40%), 256 (15), 255 (52), 205 (100), 176 (18), 174 (10), 148 (20), 138 (12), 94 (16), 91 (60), 81 (11), 79 (10), 77 (13), 68 (50), 65 (14). HRMS calculated for C19H25N2O5P: 392.1501; found: 392.1509.…”

“…1), with the type III group being the most interesting from a biochemical point of view. The preparation of phosphoramidates can be achieved by the sequential addition of amines to phosphorochloridate and treatment with alcohols or phenols, 12 the addition of amines onto phosphonic acids in the presence of dehydrating-coupling reagents, 13 the amination of phosphoryl azide, 14,15 starting from phosphorus oxychloride, 16 and employing diethyl phosphite with amines in the presence of iodine. 17 The in situ generation of alkyl azides, followed by reaction with triethylphosphite, 18 the Ophosphorylation with L-ethoxyalaninyl phosphorochloridate derivatives, 19 and the Atherton-Todd reaction between a trialkyl phosphite and a primary amine in the presence of carbon tetrachloride, 20 (or its photochemical version) 21 constitute alternative approaches to the synthesis of these compounds.…”

Bis‐Thioether‐Containing Lipid Chains in Cationic Amphiphiles: Physicochemical Properties and Applications in Gene Delivery

“…[30] As a second strategy, naturally available branched (e.g. phytanyl chains) [26,31,32] or synthetically prepared ramified (e.g. through thiol-ene click chemistry) lipid chains can be used.…”