聚乙二醇化靶向环肽的固相合成及其对阿霉素的结构修饰研究

Studies on the Solid-Phase Synthesis of PEGylated Targeting Cyclopeptide and the Modification of Doxorubicin by the PEGylated Peptides

用环肽c[CNGRC](即半胱氨酸-天冬酰胺-甘氨酸-精氨酸-半胱氨酸,其中NGR序列对肿瘤细胞有靶向作用)对阿霉素进行修饰,并且在c[CNGRC]的N端引入聚乙二醇衍生物以提高其稳定性。碘单质作为氧化剂和半胱氨酸侧链保护基的脱保护试剂,在将两个半胱氨酸的侧链保护基脱除的同时将两个巯基氧化形成二硫键,而不影响其他保护基团,从而实现在树脂上对肽的环化,为多肽环化提供了一种高效便捷的方法。多肽合成、聚乙二醇修饰及环化反应均采用固相合成法并优化了反应条件。将所制备的甲基六聚乙二醇乙酸和己酸修饰的CNGRC环肽在EDC/HOBT/NMM作用下与阿霉素连接,合成了具靶向潜力的阿霉素衍生物。

Novel doxorubicin derivatives with potential targeting to tumor cells by modifying doxorubicin using PEGylated targeting cyclopeptides were synthesized.Peptide synthesis,PEGylation and oxidation-cyclization were all realized on the resin by solid-phase synthesis and the synthetic conditions were optimized.Doxorubicin was modified by cyclopeptide(c[CNGRC],Cysteine-Asparagine-Glycine-Arginine-Cysteine;NGR sequence has targeting to tumor cells),and a polyethylene glycol group was introduced to N-terminus of c[CNGRC]to improve its stability.Iodine removes the sidechain-protecting group of the two cysteine and oxidizes sulfhydryl groups to form a disulfide bond at the same time.It provides an efficient and convenient method for the synthesis of cyclopeptides.Two PEGylated cyclopeptides were prepared under the optimal conditions and connected with doxorubicin using EDC/HOBT/NMM to provide the doxorubicin derivatives with potential targeting to tumor cells.