Molecular modeling study of a degradable element for biomedical polymers

Novel, aqueous soluble, biomedical polymers have recently been prepared that are designed to undergo enhance rates of hydrolysis at a specific degradable element at pH values less than that observed in blood circulation (i.e. pH 7.4). The degradable element in the polymer mainchain is derived from aconityl acid and is defined by a carboxylic acid pendent chain (C-4) that is cis across a double bond to an amide at C-1 in the polymer mainchain. A carboxylic acid spatially positioned to an amide in this fashion can cause enhanced hydrolytic degradation of the amide at mildly acidic pH values by assisted intramolecular catalysis from the carboxylic acid. To ensure complete degradation of the degradable element the amide bond at C-6 also must be hydrolysed. We are interested in determining by molecular modeling studies what structural features are necessary at C-2 and possibly C-5 which would enhance the rate of assisted hydrolysis by the C-4 carboxylic acid group at the C-6 amide. The aconityl derived degradable element was evaluated in two polymers with different repeat unit using molecular mechanics and dynamics, semiempirical quantum chemistry and ab initio methods. The purpose of these preliminary studies is to evaluate the shape, steric interactions and electronic effects of this degradable element within the polymer. Comparison between conformation of degradable monomers within a short chain and a long chain will also be discussed.