Synthesis and transfection properties of a series of lipidic neamine derivatives.

With the view to develop novel bioinspired nonviral vectors for gene delivery, we synthesized a series of cationic lipids with a neamine headgroup, which incorporates rings I and II of the natural antibiotic aminoglycoside neomycin B. Indeed, we reasoned that neamine might constitute a straightforward and versatile building block for synthesizing a variety of lipophilic aminoglycosides and modulating their characteristics such as size, topology, lipophilicity, number of charges, and charge density. Neamine derivatives bearing long dialkyl chains, one or two neamine headgroups, and four to ten protonatable amine functions were prepared through the selective alkylation of the 4'- or 5-hydroxyl function in ring I and ring II of neamine, respectively. The transfection activity of the twelve derivatives synthesized was investigated in vitro in gene transfection experiments using several mammalian cell lines. The results allowed us to unveil interesting structure-activity relationships and to identify a formulation incorporating a small neamine derivative as a highly efficient gene delivery system.