Study Of Enzymatic Synthesis And Modify Of Nucleoside Drug

It is more interesting topic to synthesize nucleosides derivatives because of their potent antitumor and antiviral activities. The sugar moiety and heterocyclic base of nucleosides contains several functional groups with similar chemical reactivity, so it is difficult to obtain the single product by pure chemistry without protect/diprotect steps. Enzymatic synthesis is increasingly being used in selective structural modification of nucleosides due to high selectivity and mild reaction conditions.This thesis focused on the synthesis of nucleoside mutual prodrugs and nucleoside prodrugs making use of high regio-selective of enzyme in nonaqueous organic solvents. Eleven nucleoside derivates were synthesized by enzymatic regio-selective reaction in nonaqueous organic solvents using three divinyl dicarboxylates as acyl-donor and several typical nucleoside and its analogs as acyl-receptor (ddI, 2'-deoxyuridine, 5-flunucleoside). All the products was new derivate tested by IR, NMR and MS. As to the investigation of the importance of reaction medium, six solvents and six enzymes were discussed. From the result, lipase in low-pole solvent, such as dioxane, acetone and THF, showed good activity, but in high-pole solvent (DMF and pyridine) was low activity.A reasonable reaction route for regioselective enzymatic synthesis of mutual prodrugs from two drugs with interconnected cytotoxic activity in nonaqueous organic solvents was designed. Three batyl alcohol derivates were synthesized from fatty acid divinyl ether with batyl alcohol, and then six mutual prodrugs were obtained by further enzymatic transetherification with nucleoside drug (ddI or acyclovir) in nonaqueous organic solvents. All the products was new derivate tested by IR, NMR and MS.This thesis also developed an effective way of controllable regioselective enzymatic acylation for different hydroxyl groups of 2'-deoxyuridine. Lipozyme in acetone showed high regioselective acitivity for primary hydroxyl, and in dioxide high for secondary hydroxyl of 2'-deoxyuridine. PPL in acetone and THF also showed high regioselective acitivity for secondary hydroxyl. So the different acyl-products could be obtained by controlling the condition of enzymatic reaction.