Drug Derivatization By Enzymatic Methods And Preparation Of Optically Pure Drug And Polymeric Prodrug

Enzymatic methods play an important role in the synthesis of pharmaceutical compounds and their derivatives due to their high selectivity and mild reaction conditions. In this thesis, selective enzymatic synthesis of some drug derivatives, such as nucleoside drugs, non-steroidal anti-inflammatory drugs (NSAIDs) were developed.The selective enzymatic synthesis of some drugs derivatives containing multi-hydroxyl in non-aqueous media was developed. Cytarabin, Ribavirin, Inosine and Guaifenesin were chosen as substrates. Divinyl dicarboxylates and fatty acid vinyl esters with different carbon length were used as donor agents. 19 kinds of polymerizable vinyl esters and 24 kinds of fatty acid ester derivatives of drug were selectively prepared in good yields through enzymatic reaction. Moreover, the influence factors of enzymatic synthesis such as enzyme sources, reaction media, water content, reaction time were investigated.The controllable selective synthesis of cytarabine derivatives could be achieved. Catalysis by lipase acrylic resin from Candida antarctica (CAL-B) in acetone could facilitated the single step synthesis of polymerizable 5'-O-acyl cytarabine derivatives in high yields. The application of alkaline protease from Bacillus subtilis (Subtilisin) in pyridine afforded the mixture products of 5'-O-acyl and 4-N-acyl cytarabine derivatives. 4-N-acyl cytarabine vinyl derivatives can be selectively prepared by chemical transesterification. The controllable selectivity of different position of cytarabine was achieved by change reaction condition.Selective enzymatic synthesis of drug derivatives containing carboxyl group in non-aqueous media was also developed. Enzymatic acylation of vinyl esters of ketoprofen, indomethacin and etodolac with different sugar or sugar alcohols (mannitol, glucose, mannose, galactose, lactose, maltose, sucrose) were developed to prepare 11 kinds of NSAIDs derivatives containing sugar, which showed better water solubility. The reaction conditions, water-solubility, in-vitro release and in-vivo pharmacological activity of 6-O-ketoprofen glucose ester were also investigated, and the results suggested that 6-O-ketoprofen glucose can be considered as a promising prodrug form.The chemo-enzymatic method for preparation of optically active ketoprofen polymeric prodrug and ribavirin polymeric prodrug was developed. Lipase-catalyzed synthesis of polymerizable S-ketoprofen vinyl ester, ribavirin vinyl ester and 17 kinds of ketoprofen polymeric prodrugs and ribavirin polymeric prodrugs were obtained. The products were characterized by IR, NMR and GPC. A series of copolymers containing ketoprofen monmers and methyl methacrylate or acrylonitrile or acrylic amide had high molecular weight. After optimization of polymerization conditions, it was found that the optimal molar ratio of ketoprofen vinyl ester to methyl methacrylate is 1/2, and the content of polymerization initiator was 0.02 (w/w)...