ИСТИНА

2,5-Diketomorpholine derivatives and esters of N-oxyacylated amino acids could be promising monomers for the enzymatic synthesis of biodegradable polyesteramides (polydepsipeptides). Polydepsipeptide-based bioresorbable polymers can possess different functional properties and be used in controlled drug release systems, tissue engineering scaffolds and as shape-memory materials [1]. Polyesteramides as well as polyesters are prepared by consequtive ester bond-formation reactions employing two major approaches: ring-opening polymerization of cyclic monomers such as 2,5-diketomorpholines and polymerization via condensation of a carboxylic acid (or its ester) and an alcohol group of bifunctional monomers [2]. Lipases are most commonly used as biocatalysts to prepare polyesteramides by ring-opening polymerization of cyclic monomers [3]. Earlier we have reported a chemoenzymatic procedure of the stereoselective synthesis of 2,5-diketomorpholine derivatives and esters of N-oxyacylated amino acids [4]. In this work, we have investigated the possibility to use the earlier synthesized compounds as monomers for lipase-catalyzed polymerization applying molecular modeling as well as experimental studies. Molecular docking has shown that lipase B from Candida antarctica is capable of forming reactive enzyme-substrate complexes with both 2,5-diketomorpholine derivatives and esters of N-oxyacylated amino acids. The calculated binding energies were −8 ÷ −6 kcal / mol. Different lipase preparations have been also tested experimentally for their ability to convert these substrates. The activity of each enzyme preparation was studied experimentally using N-(R)-mandelyl-(S)-phenylalanine methyl ester and (3S,6S)-3-benzyl-6-phenylmorpholine-2,5-dione as model substrates in the biphasic system toluene-aqueous phosphate buffer. It was shown that lipases can catalyze the transformation of previously unexplored substrates. The methodology to track biocatalytic polymer synthesis based on the analysis of the molecular mass distribution of the reaction products using exclusion chromatography has been developed and optimized. This work was supported by the Russian Foundation for Basic Research (grant 17-08-01637) 1. Feng Y., Guo J. Biodegradable Polydepsipeptides, Int. J. Mol. Sci., 2009, 10, 589-615 2. Kobayashi S. Lipase-catalyzed polyester synthesis – A green polymer chemistry, Proc. Jpn. Acad. Ser. B Phys. Biol. Sci., 2010, 86, 338-365 3. Feng Y., Klee D., Keul H., Höcker H. Lipase-catalysed ring-opening polymerization of morpholine-2,5-dione derivatives: A novel route to the synthesis of poly(ester amide)s, Macromol. Chem. Phys., 2000, 201, 2670-2675 4. Nikulin M.V., Misiura N.M., Švedas V.K. Stereoselective chemoenzymatic synthesis of 2,5-diketomorpholines. Abstracts of 11th International Conference “Biocatalysis: Fundamentals and Applications” / Editors Tishkov V. and Fedorchuk V. – Moscow: Innovations and High Technologies MSU Ltd, 2017, 88-89