Structure-property relationships of d-mannitol-based cationic poly(amide triazoles) and their self-assembling complexes with DNA

Abstract

A set of poly(amide triazoles) (PT) was synthesized by azide-alkyne cycloaddition reactions from N,N-Bis[2-(propargylamido)ethyl]-N-[2-(tert-butoxycarbonylamino)ethyl] amine and 1,6-diazido-1,6-dideoxy-d-mannitol derivatives, having the secondary hydroxyl groups protected by removable acetal and/or acetyl groups. Either copper-catalyzed (CuAAC) as well as the classical thermal cycloaddition reactions were used to afford in good yields and medium molecular weight-linear PT featuring either 1,4- or 1,4/1,5-disubstituted triazole rings along the polymer chains, respectively. Full structural characterization of all PT was accomplished and comparatively studied. Protecting group removal allowed for modulating the flexibility and polarity of cationic polytriazoles (CP), entitling for structure-activity relationship insight of their self-assembling capabilities in the presence of nucleic acids. Hence, CP and DNA were formulated at different nitrogen-to-phosphate (N/P) ratios and the resulting polyplexes were characterized by Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM). All CP were able to condense DNA into positively-charged nanometric-sized and narrow-polydispersed particles that could mediated transfection into human embryonic stem cells (hESC) with negligible toxicity.