Hydrophilic Poly(N-Acyldehydroalanines) Containing Asymmetric Nucleic Acid Base Derivatives as Pendant Groups: Synthesis, Characterization, and Antiviral Activity (Polyanion, Polymer, Polynucleotide, Polymer Chemistry).

A new family of asymmetric nucleic acid base-containing monomers, namely the 2-{2-(adenin-9-yl), (uracil-1-yl), and (thymin-1-yl)propanoamido}propenoic acids and their methyl esters were prepared starting from the 2-nucleopropanoic acids and (beta)-chloroalanine methyl ester. These dehydroalanine derivatives were polymerized by free radical or (gamma)-radiation initiation in solution to give high molecular weight, hydrophilic polynucleotide analogs. When (-)-2-(thymin-1-yl)propanoic acid was used as a starting material, optically active monomers and polymers were obtained. Appropriate monomer model compounds were prepared and an approach to the dimer models was investigated. Several novel bis- and tris(dehydroalanines) were prepared which effectively crosslinked the monomers, so that hydrophilic, thymine-containing resins were obtained. Such a resin was used to separate an aqueous mixture of nucleosides using the complementary hydrogen bonding interaction between purines and pyrimidines. The solution properties of the linear polynucleotide analogs were examined by gel permeation chromatography, light scattering, potentiometric titrations, and viscosity, as well as high resolution proton magnetic resonance, ultraviolet, and circular dichroic spectroscopies. By analogy with the single-str and ed polynucleotides, the polymers showed base stacking behavior in aqueous solution. This stacking resulted in significant UV hypochromicities and differences in the NMR spectra in comparison with the monomer models. The polyacids behaved as severely hindered polyelectrolytes; their conformational rigidity was apparent from the titration and spectroscopic data. As a result, the polymers showed only weak base pairing interactions. The water soluble polyacids possessed antiviral activity when tested in tissue culture against a number of viruses of interest in human diseases. Although the mechanism for this activity was not certain, the rigid conformation and dense array of negative charges present in these polymers appeared to be important.PhDPolymer chemistryUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/160271/1/8502771.pd