Polyphosphazenes that contain dipeptide side groups: Synthesis, characterization, and sensitivity to hydrolysis

The dipeptides alanyl-glycine ethyl ester, valinyl-glycine ethyl ester, and phenylalanyl-glycine ethyl ester were synthesized by mixed anhydride solution-phase peptide reactions. The free N-terminus was used as a reactive site for nucleophilic replacement of the chlorine atoms in poly(dichlorophosphazene). The C-terminus was protected with an ethyl ester to prevent side reactions and cross-linking. The alanyl-glycine ethyl ester replaced all the chlorine atoms in poly(dichlorophosphazene). However, replacement of all the chlorine atoms in poly(dichlorophosphazene) by valinyl-glycine ethyl ester or phenylalanyl-glycine ethyl ester polyphosphazenes was prevented by the insolubility of the partially substituted intermediates. To circumvent this problem, cosubstitution was carried out using the valinyl- or phenylalanyl esters with glycine ethyl ester or alanine ethyl ester in a 1:1 ratio. Cosubstituted polyphosphazenes with alanyl glycine ethyl ester and glycine ethyl ester or alanine ethyl ester were also synthesized with a side group ratio of 1:1. The polymer structures and physical properties were studied using multinuclear NMR, DSC, and GPC techniques. Heterophase hydrolysis experiments in aqueous media at different pH values were carried out to estimate the hydrolytic sensitivity of these polymers. All the polymers were less sensitive to hydrolysis under neutral or basic (pH, 10.0) conditions than at pH 4.0, where rapid hydrolysis occurred.