Biosynthetic stereocopolymer of 3-methylmalic acid as hydrolyzable and biocompatible polyester for temporary therapeutic applications

A mixture of (2S,3S) and (2S,3R)-3-methylaspartic acid, obtained by bioconv ersion of mesaconic acid in the presence of 3-methyl-aspartase as enzymatic catalyst, was transformed into the corresponding benzyl 3-methylmalolacton ate stereoisomers using a multiple-step synthesis. A mixture of (3R,3R) and (3S,4R) (80/20 (mol/mol) ratio) benzyl-3-methylmalolactonate was transform ed by anionic ring-opening polymerization to an optically active and stereo regular stereocopolymer constituted by 80 mol% of benzyl (3R,3S) 3-methylma late repeating units and 20 mol% of benzyl (3S,4S) 3-methylmalate units, as determined by H-1 NMR. The corresponding optically active poly(beta-3-meth ylmalic acid) was obtained by catalytic hydrogenolysis of the protecting be nzyl ester groups, in N-methylpyrrolidone as solvent. This functionalized h ydrosoluble polyester was degraded by simple hydrolysis in a phosphate buff er at pH 7, as shown by SEC measurements. It is worth noting that the kinet ic profile was equivalent to the one of poly(P-malic acid). Moreover, at 37 degrees C, the hydrolysis was complete within six weeks, yielding to the c orresponding optically active 3-methylmalic acid. In order to use this poly meric material for temporary therapeutic applications, polymers containing both diastereoisomers as repeating units as well as their ultimate products of degradation were evaluated based on harmlessness towards their environm ent. No toxicity was detected against a human cell line, HepG2. (C) 1999 El sevier Science Ltd. All rights reserved.