Nucleic acid base grafted poly(ethylenimine): Polynucleotide analog and therapeutic agent

Abstract

Poly(N-acyl ethylenimine) of various molecular weights was synthesized by the cationic ring-opening polymerization of 2-H-2-oxazoline and 2-methyl-2-oxazoline. Acid hydrolysis afforded the linear poly(ethylenimine) which was used in the following grafting reactions. Vapor pressure osmometry, gel permeation chromatography and viscosity measurements were used to characterize the polymers synthesized. Potassium 2-(cytos-l-yl) propanoate and potassium 3-(cytos-l-yl) butanoate were synthesized in good yield from thenucleic acid base. These cytosyl pendant groups were grafted onto the poly(ethylenimine) using 4-chloro-1-(4-chlorobenzenesulfonyl) benzotriazole, 90% graft, and norborn-5-ene-2,3-carboximido diphenyl phosphate, 70% graft. Grafting of the t -butoxycarbonyl and n -butoxycarbonyl protected cytosyl pendant groups resulted in a 47% graft. Hypochromicity studies indicated an ordered structure at the local level. The secondary structure is a base-stacked conformation. Light scattering results gave insight into the tertiary structure of the macromolecule. The polymer exists in solution as stiff chains, rod-like in nature. Continuous mixing experiments were carried out with polyribonucleotides. The Job plots indicated increased level of ordered conformation with either an increase in the molecular weight or an increase of the base to base distance in the analog. Enhancement in the base-stacked conformation was higher in the polyinosinic acid complex than that of the polyguanylic acid complex.