Mannich型环肽的液相及固相合成比较  

Comparative Synthesis of Mannich-Type Cyclopeptides between Solution-Phase and Solid-Phase Protocols

作　　者：刘洪强[1] 林浩[1] 田桂杰[1] 王德心[1] 

机构地区：[1]中国医学科学院药物研究所,北京100050

出　　处：《有机化学》2003年第8期804-808,共5页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金 (No.30 2 71 530 )资助项目

摘　　要：为了改善肽化合物的抗酶解能力 ,首次介绍了 3肽Pro Pro Tyr分子的非天然环化反应 .其中分别采用液相及固相两种合成方式组装直链肽 ,再经过分子内Mannich缩合 ,得到以Mannich碱为桥连结构的环肽 5 (产率 5 3 8% )及 10 (产率72 7% ) .产物结构经氨基酸组分及质谱分析证明 .结果表明 ,固相法环合可以避免分子间反应 ,因此产物收率明显高于液相法 .It is well known that the short half-life of peptides in vivo can be dramatically prolonged by chain-cyclization with a conformationally constrained feature. Compared to the disulfide bonding or amide bonding cyclopeptides, an increasingly attraction in research on developing drug candidates is the design of unnatural structure hybridized cyclopeptides. Herein, the first synthesis of Mannich base bridged cyclopeptides by both solution-phase and solid-phase protocols is reported. Generally, aldehyde, amine and active-hydrogen component are the necessary building blocks for Mannich condensation. In present study, two of three Mannich's components, the N-terminal aminogroup and the Tyr residure (served as the active hydrogen components) were assembled in the peptide substrate before reacting with the third component formalin, ensuring the formation of cyclo-Mannich base. As a result of the total yield (72.7%) of the product 10 from solid-phase protocol is much higher than the yield (5.38%) of product 5 from solution-phase procedure, the pseudo-dilution effect concerned with solid-phase should be responsible for the intra-molecule condensation, avoiding from inter-molecule condensation. Therefore, present protocol would be a pragmatic way to prepare some unnatural structure hybridized cyclopeptides.

关 键 词：Mannich型环肽 液相合成 固相合成 假稀释原理 非天然环化反应 肽化合物 质谱分析 

分 类 号：O629[理学—有机化学]