Synthesis And Properties Of Acyclovir-oligopeptide Derivatives

Acyclovir (ACV) of cyclic nucleoside widely used therapeutic agent for the treatment ofherpes virus infection. However, ACV suffers from low aqueous solubility and lowbioavailability, the average oral bioavailability of acyclovir is fairly low (only10~20%) andits plasma elimination half-life is merely2.5~3.3h. To overcome this problem, many kinds ofdrug carrier coupling agents have been utilized to improve and enhance curative effect.As a good drug carrier, oligopeptides has good water solubility, but also could use theoligopeptide transporter PepT to improve the drug bioavailability and reduce the drug toxicity.This thesis mainly includes the following points:1. The single factor experiment and orthogonal design were applied to the optimize thesynthesis of SACV, a water-soluble prodrug of ACV. The optimal conditions were as followed:the molar ratio of ACV and succinic anhydride is1:2, the reaction temperature is50℃, theweight ratio of triethylamine with succinic anhydride is0.53, the reaction time is21hours in75mL DMF, acidification pH value is2. The yield of SACV increases from45.4%to63.3%.2. Ten new ACV-peptide derivatives (SACV-Gly-Ala, SACV-Glu-Ala, SACV-Lys-Ala,SACV-Val-Lys, SACV-Glu-Lys, SACV-Val-Gly, SACV-Gln-Gln, SACV-Phe-Ala,SACV-Gly-Phe, SACV-Val-Val-Val) were designed and synthesized by the Fmoc solid phasesynthesis, which is the first reported method on synthesis SACV-oligopeptide compounds.These compounds were purified by RP-HPLC and characterized by ESI-MS,1H NMR.3. Fomc Solid-phase synthesis is famous for simple experiment process, less toxicreagents and higher yield. This provides a good example for the synthesis ofACV-oligopeptide derivatives.4. ACV-peptide derivatives properties such as the water-solubility, oil-water partitioncoefficient and metabolic properties in vitro were investigated. The results show that thesolubility of both SACV and ACV-oligopeptide derivatives are greatly improved; bothsolubility and oil-water partition coefficient acyclovir-oligopeptide derivatives containeddipeptide, which is composed acidic amino acid and alkaline amino acids, are increased; TheACV peptide analogs are in line with the first-order kinetic equation at the pH7.4and pH1.2in the kinetic degradation process, the release ACV rate is faster in pH7.4than that in pH1.2;the degradation speed of ACV peptide analogs have a direct relationship with the structure ofthe adjacent amino acid. Larger steric hindrance, more stable and longer half-life.SACV-Glu-Lys and SACV-Val-Gly have good physical and chemical properties, compared with other ACV peptide analogs.