Enzymatic Or Chemical Synthesis Of Nucleoside Derivatives And Polymeric Prodrugs

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 nucleoside drug derivatives was developed.The selective enzymatic synthesis of some nucleoside derivatives containing multi-hydroxyl in non-aqueous media was developed. 2'-deoxy-5-fluorouridine, 5-fluorouridine, 5-fluorocytidine and 5'-deoxy-5-fluorouridine were chosen as substrates. Divinyl dicarboxylates with different length of carbon chain were used as acyl donor. Polymerizable vinyl esters derivatives of drugs were selectively prepared in good yields and selectivity through enzymatic reaction. Moreover, the influence factors of enzymatic synthesis such as enzyme sources, reaction media, water content, reaction time, temperature were investigated.The controllable selective synthesis of 2'-deoxy-5-fluorouridine derivatives could be achieved. Catalysis by lipase acrylic resin from Candida antarctica (CAL-B) in THF or alkaline protease from Bacillus subtilis (Subtilisin) in pyridine could facilitate the single step synthesis of polymerizable 2'-deoxy-5-fluorouridine derivatives in high yields. The controllable selectivity of different position of 2'-deoxy-5-fluorouridine was achieved by change reaction conditions. Furthermore, selective acylation of primary hydroxyl of 5-fluorouridine and 5-fluorocytidine was achieved. The reaction was catalyzed by CAL-B in THF. And the enzymatic selective acylation of 5'-deoxy-5-fluorouridine was under investigation, too.Floxuridine-saccharide and 5-fluorouridine conjugates, which are potential targeting drugs, were obtained from vinyl nucleoside esters by enzymatic methods. The reactions were catalyzed by Subtilisin in pyridine. The reactions were started from D-Glucose, D-Mannose, D-Galactose.Synthesis of polymeric prodrugs of nucleosides was achieved by chemical polymerization initialed by AIBN in DMF. Moreover, nucleoside-PEG adducts were obtained by enzymatic methods. The reactions were initiated by CAL-B in THF.