Molecular modeling study of a degradable element for biomedical polymers

Novel, aqueous soluble, biomedical polymers have recently been prepared tha t are designed to undergo enhance rates of hydrolysis at a specific degrada ble 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 a conityl acid and is defined by a carboxylic acid pendent chain (C-4) that i s cis across a double bond to an amide at C-1 in the polymer mainchain. A c arboxylic acid spatially positioned to an amide in this fashion can cause e nhanced hydrolytic degradation of the amide at mildly acidic pH values by a ssisted intramolecular catalysis from the carboxylic acid. To ensure comple te 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 a t the C-6 amide. The aconityl derived degradable element was evaluated in t wo polymers with different repeat unit using molecular mechanics and dynami cs, semiempirical quantum chemistry and ab initio methods. The purpose of t hese preliminary studies is to evaluate the shape, steric interactions and electronic effects of this degradable element within the polymer. Compariso n between conformation of degradable monomers within a short chain and a lo ng chain will also be discussed.