Selective alkylation and bioactivity of phosphorothioated nucleolin aptamer AS1411  

核酸适配体AS1411的磷硫骨架烷基化修饰及其生物学性质研究（英文）

作　　者：张光普[1] 邓家荔 杨先桃[1] 朱月洁[1] 关注[1] 张礼和[1] 杨振军[1] 

机构地区：[1]北京大学医学部药学院天然药物及仿生药物国家重点实验室,北京100191

出　　处：《Journal of Chinese Pharmaceutical Sciences》2017年第1期23-30,共8页中国药学（英文版）

基　　金：the Ministry of Science and Technology of China(Grant No.2012CB720604);National Natural Science Foundation of China(Grant No.21332010)

摘　　要：An operationally simple and efficient method for the synthesis of a wide range of alkylated nucleotides under mild conditions was developed. This improved method furnishes alkylated nucleotides fi＇om both single nucleotides and oligonucleotides, and were prepared in high yields of 81% to 91%. Alkyl modified aptamer AS1411s were synthesized using this method and the biological activity screening results demonstrated that alkylation at the 1^st P-S site on yielded stronger target protein binding capacity, greater growth suppression effects against K562 and HL-60 cell lines, and improved serum stability, as compared with AS1411. This modified aptamer may be useful in tumor detection and treatment.对寡核苷酸进行恰当的化学修饰可以提高其稳定性并增加其生物学活性。该研究探索了一种以PBS缓冲液(p H 7.4)及甲醇作为溶剂在温和条件下进行核酸磷硫骨架烷基化修饰从而引入烷基功能基团的高效绿色化学合成方法,可以同时适用于硫代单核苷酸及寡核苷酸磷酸骨架硫代位点的烷基化修饰,其综合产率为81%–91%。利用该方法设计合成烷基化修饰的核酸适配体AS1411s,生物学评价发现1位磷硫(PS)烷基化修饰的AS1411可提高其与靶蛋白作用能力和血清稳定性,并表现出较强的K562和HL-60肿瘤细胞生长抑制作用。磷硫骨架烷基化修饰的核酸适配体AS1411s可以作为潜在的肿瘤检测剂与治疗药物进行更深入的研究。

关 键 词：Phosphorothioated nucleotide ALKYLATION APTAMER AS 1411 NUCLEOLIN 

分 类 号：R914[医药卫生—药物化学]