Enzymatic Synthesis Of Nucleoside Derivatives And Preparation Of PH-sensitive Polymeric Prodrugs

It is more interesting topic to synthesize nucleosides derivatives because of their potent antitumor and antiviral activitied. 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 polymerizable drug derivatives, preparation of pH-sensitive polymeric prodrugs with acrylic acid and acrylamide, and investigation of these pH-sensitive polymers were developed.The selective enzymatic synthesis of some nucleoside derivatives in non-aqueous media was developed. Cyrarabin and 5-azacytidine were chosen as substrates. Dininyl dicarboxylates with different carbon length were used as donor agents.12 kinds of polymerizable vinyl esters of drugs were controllable selectively prepared in better yields through enzymatic reaction. The structures of all the derivatives were confirmed using FT-IR and NMR. Moreover, the influence factor of enzymatic synthesis such as enzyme sources, reaction media, reaction time, temperature were investigated.The controllable selective synthesis of cytarabine derivatives could be achieved. Lipase acrylic resin from Candida Antarctica (Novozym 435) in anhydrous acetone showed comparable high chemo-selectivity toward the 5'-OH in good yields of 69%. However, lipase PS IM Amano in pyridine selectively acylated the amino group and the yield of 4-N-vinyladipate cytarabine reached 58%. So the different acyl-products could be obtained by controlling the condition of enzymatic reaction.Synthesis of polymeric prodrugs of nucleosides was achieved by chemical polymerization initiated by AIBN in DMF, and 15 kinds of polymeric prodrugs of cyrarabin vinyl esters and 5-azacytidine vinyl esters were obtained. And these products were characterized by IR, NMR and GPC. A series of homopolymer and pH-sensitive copolymers containing drugs monomers, acrylic acid and acrylamide had high molecular weight. The in-vitro release of homopolymer and copolymers with acrylic acid and acrylamide was investigated in PBS (pHÏ…7.4), and the results showed that the release rate of pH-sensitive copolymers was faster than homopolymer. In addition, to further understand the in-vitro release of the prodrug copolymer, the paper examined the effects of different pH conditions on the in-vitro release of polymeric drugs of 5-azacytidine vinyl esters with acrylic acid, as well as the effects of the different molar ratio of 5-azacytidine vinyl esters to acrylic acid (2:1,1:1,1:2, 1:4) the on the in-vitro release in pH 5.4 buffer solution. The results showed that the copolymer of 5-azacytidine vinyl esters to acrylic acid (1:1) displayed definitely obvious pH sensitivity in pH 5.4 buffer solution and the copolymer prodrug had the largest release rate. And acidic pH sensitivity of prodrug copolymers with a higher proportion of the acrylic acid in copolymer was enhanced.