Synthesis of Novel Cationic Lipids: Effect of Structural Modification on the Efficiency of Gene Transfer
| Autor: | Robert Geoffrey Cooper, Caroline J. Springer, Dan Niculescu-Duvaz, James Anthony Heyes |
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| Rok vydání: | 2001 |
| Předmět: |
Gene transfer
Arginine Cell Line Structure-Activity Relationship Cations Cricetinae Drug Discovery Animals Histidine Liposome Chemistry Lysine Genetic transfer Gene Transfer Techniques Tryptophan Cationic polymerization Transfection beta-Galactosidase Lipids Combinatorial chemistry Chain length Cholesterol Biochemistry Liposomes Molecular Medicine Ethers Oleic Acid |
| Zdroj: | Journal of Medicinal Chemistry. 45:99-114 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm010918g |
| Popis: | A series of novel cationic lipids was designed and synthesized in an effort to understand the importance of the various structural features with respect to transfection efficiency. Particular attention has been paid to the hydrophobic domain and the cationic headgroup. An efficient method of synthesizing asymmetric diether lipids is described, using alkyl chains ranging from C(12) to C(18) and the unsaturated oleyl group. The ternary formulations including the diether lipid 3beta-[N-(N',N'-dimethylaminoethyl)carbamoyl]cholesterol (DC-Chol) and dioleoyl phosphatidylethanolamine (DOPE) were up to 10-fold more efficacious in in vitro assays than the DC-Chol/DOPE control. The shorter and most asymmetric diether lipids performed the best. The chemical nature and basicity of the headgroups have been varied by the coupling of the four naturally occurring amino acids with cationic side chains-arginine, histidine, lysine, and tryptophan. Transfection efficiency was highest for arginine/lysine derivatives, with binary formulations containing the amino acid derivative alone and DOPE proving superior. |
| Databáze: | OpenAIRE |
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