Systematic solid-phase synthesis of linear pseudooligolysines containing multiple adjacent CH(2)NH amide bond surrogates: potential agents for gene delivery.

Solid-phase methodology was used to synthesize a series of fully reduced linear oligolysines (pseudooligolysines, abbreviated herein as PLs) containing up to five adjacent CH2NH peptide bond isosteres. The reduced peptide bonds were introduced by the reductive alkylation reaction between Fmoc-Lys-(Boc)-al and a free alpha-amine moiety on the pseudopeptidyl resin, using sodium cyanoborohydride in an acidified mixture of NMP/CH3OH (1 : 1 v/v). The oligomeric molecules, which can be regarded as polyethylene imine and spermine analogs, possess multiple positive charges under physiological conditions and form tight complexes with plasmid DNA. These characteristics and the increased resistance to hydrolysis by trypsin make these molecules potential candidates for future use as DNA carriers in gene delivery.