Homologation of polyamines in the rapid synthesis of lipospermine conjugates and related lipoplexes

Lipopolyamine amides are useful cationic Lipids, synthetic vectors for non- viral gene delivery. Desymmetrisation of readily available symmetrical poly amines is an important first step in the synthesis of such compounds. The a pplication of trifluoroacetyl as a protecting group allows unsymmetrical po lyamine amides to be rapidly prepared. A reductive alkylation homologation strategy allows the sequential, regiocontrolled introduction of additional positive charges. Tetraamine spermine and other polyamine derivatives have been N-1-acylated with various single alkyl chains, and their relative bind ing affinities for DNA determined using an ethidium bromide displacement as say. The important effects on DNA binding affinity of the number of positiv e charges on the polyamine moiety and also the nature (chain length and deg ree of unsaturation) of the covalently attached lipid are demonstrated. (C) 2000 Elsevier Science Ltd. All rights reserved.