Pyridinium-Based Cationic Lipids as Gene-Transfer Agents

• Published in: European journal of organic chemistry 2003-07, Vol.2003 (14), p.2645-2655
• Main Authors: Ilies, Marc Antoniu, Seitz, William A., Caproiu, Miron T., Wentz, Melissa, Garfield, Robert E., Balaban, Alexandru T.
• Format: Article
• Language: English
• Subjects: Cationic lipids; Gene-transfer agents; Liposomes; Nitrogen heterocycles; NMR spectroscopy; Transfection
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200300106

Cationic lipids are a promising alternative to viral vectors for gene therapy, allowing the delivery of larger plasmids without immunogenicity, despite their lower transfection efficiency. Among them, heterocyclic systems with imidazolium or pyridinium polar head groups have definite advantages such as the excellent transfection profiles and low cytotoxicity. Our approach for synthesizing heterocyclic cationic lipids differs from those previously described because we synthesize a pyridinium ring from simple starting materials. First a pyrylium salt is formed via diacylation of alkenes. The pyrylium salt is then converted by primary amines into pyridinium salts. Appropriate choice of the primary amine allows the attachment of two hydrophobic chains yielding compounds 21A and 25A (with various chain lengths derived from palmitic, stearic and oleic acids). The same strategy allowed the preparation of lipophilic derivatives 21B, 25B useful as strongly fluorescent markers for the study of the properties of biological membranes. Preliminary tests with some of the compounds 21A and 25A, on several cell lines, showed comparable transfection efficiencies and lower cytotoxicity than those obtained with standard commercial transfection agents. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)