We reported earlier a new class of pyridinium cationic lipids in which the polar head and the linker are synthesized simultaneously from pyrylium salts and primary amines. Subsequent acylation with fatty acid chlorides yielded the final cationic lipids. A new one step synthesis is reported from lipophilic pyrylium salts 1 and long-chain amines yielding new pyridinium transfection agents 2. Gemini lipids 3 were obtained from the same pyrylium salts with various diamines or polyamines. A structure-activity relationship study was carried out to identify the structural parameters required for best transfection efficiency.

The optimization of the lipoplex properties and their efficiency on several tumor cell lines is discussed. Incorporation of biodegradable (ester, amide) or reduction-sensitive linkages (S-S bonds) in the structure of the lead compounds reduced the cytotoxicity and enhanced the transfection efficiency by overcoming the intracellular delivery barriers. The most efficient second-generation vectors are presented, together with their biological data.