Synthesis of novel exocyclic amino nucleosides by parallel solid-phase combinatorial strategy

A versatile parallel solid-phase combinatorial strategy was developed for the synthesis of large nucleoside libraries. Twelve libraries L1-12 of 1152 novel exocyclic triazinylamino nucleosides and one library L13 of 82 new substituted clitocine derivatives were synthesized in high quality as natural product mimic nucleosides on the semi-automated synthesizer. The polystyrene MMT-Cl resin was selected and utilized. The key intermediate resins 5 and 9 loaded with the corresponding scaffolds were prepared and validated with various amines before parallel synthesis. After a variety of amino building blocks were validated, 56 primary amines in 12 groups (building block set A) and 24 secondary amines in 3 groups (building block set B) were selected and utilized to combinatorialize the first and the second reactive sites on scaffold 5 for the synthesis of libraries L1-12. Eighty-two amines (building block set C) were utilized for the synthesis of clitocine library L13. Thirteen libraries of 1234 novel exocyclic amino nucleosides were all analyzed and characterized by high throughput LC-MS. 81.3-100% of the library members in 13 libraries show more than 60% purity, and 65.7-92.7% of the library members in these libraries show 80-100% purity. The strategy can be widely used for the synthesis of other diverse nucleoside libraries.     

克力托辛(Clitocine)及其类似物的合成与生物活性

克力托辛是一种从蘑菇Clitocybe inversa中分离出的天然核苷.它及其类似物具有很高的生物活性.综述了克力托辛及2'-脱氧克力托辛类似物、碱基修饰克力托辛类似物、5'-脱氧克力托辛类似物、碳环克力托辛类似物以及无环克力托辛类似物的合成方法,并对克力托辛及其类似物在农业害虫杀灭、腺苷激酶抑制剂、抗肿瘤、抗病毒等药物研究中的应用进行了概述.