新型酶催化Ugi三组分反应物理法诱导合成功能性环肽的研究

Cyclic peptides have received extensive attentions in chemistry, biology, materials science and medical science due to their outstanding biological activities and metabolic stabilities. The synthesis of cyclic peptides has become the research highlight of peptide chemistry, and current strategies of cyclic peptide synthesis mainly utilize amino acids as starting materials, non-amino acid route has seldom been reported. In this project, enzyme-catalyzed three component Ugi reaction is employed to synthesize dipeptides, which are later to condense by ester exchange reactions. The driving force of peptides cyclizing arises from two aspects: the translational entrapy increase of water in the folding of linear peptide precursors, and the hydrogen bonding interactions between peptide precursors and solvents. These forces provide the required restricted conformation before the cyclizing of linear peptides. This novel reaction system combines simple components to construct complicated molecular structures, it significantly expands the methodology of cyclic peptide synthesis, simplify the operation procedure and reduce the cost. In addition, this method makes a breakthrough to realize chemical synthesis of cyclic peptides under high concentration by micelle-like structure in selective solvents. This project not only plays an important role in the revolution of cyclic peptide synthesis, but also gives contributions to establishing novel approaches for building complicated molecular structures.

环肽凭借优异的生理活性和代谢稳定性在化学、生物、材料、医药等领域得到了广泛的关注，环肽的合成逐渐成为多肽化学的研究热点。国内外环肽的合成主要依赖于氨基酸缩合法，非氨基酸法合成环肽鲜有报道。本项目拟采用酶催化Ugi多组分反应合成二肽，利用酶的酯交换催化性能实现二肽单元的扩链，并利用肽链折叠过程中水分子平移熵的增加和直链肽前体及溶剂之间的氢键相互作用提供直链肽环合所需的受限构象，作为直链肽环合的驱动力以合成功能性环肽。此反应体系有效地简化了环肽的制备流程，有效降低了制备成本，大大拓展了环肽合成的方法学。同时，借助选择性溶剂中直链肽的类胶束结构，此方法很好地解决了环状分子合成所依赖的高稀浓度环境这一难题，实现了液相合成中高浓度下合成环肽的技术突破。本项目不仅对环肽合成技术的变革具有重大的推动作用，对功能分子复杂结构的模型构建也具有重要的借鉴意义。

环肽在结构坚固性、细胞跨膜性、代谢稳定性等方面的优势显著提高了多肽的成药性，因此环肽的合成一直是药物化学的研究热点。传统环肽的合成方法主要基于氨基酸缩合法，需要多次保护-脱保护的繁琐工艺。另一方面，受限于反应和催化剂，非氨基酸法合成环肽的进展非常有限。本项目中，我们首先采用酶催化Ugi多组分反应合成末端基团分别为氨基和酯基的二肽，进而在脂肪酶的催化下发生酯交换反应进行扩链或关环，生成相应的直链肽和环肽。研究发现，等当量的二胺、异腈和醛在脂肪酶的催化下，在水中室温反应24小时后均能得到不同聚合度的环肽库。相应环肽的产率与二胺和醛的种类密切相关，位阻较大的二胺和醛由于受限的空间构象，更有利于环肽的生成。其次，水相中环肽的产率要高于氯仿相，我们推测肽链折叠过程中水分子平移熵的增加和直链肽前体及质子溶剂之间的氢键相互作用提供了直链肽环合所需的受限构象，作为直链肽环合的驱动力。此外，酶催化Ugi多组分反应合成环肽的体系中，直链肽的类胶束结构使其在高浓度下依然能高效地成环，解决了环状分子合成所依赖的高稀浓度这一难题。同时，研究发现空间位阻较大的环肽具有非典型性荧光特性。综上所述，本项目不仅为环肽的非氨基酸法合成提供了一种简易可行的新路线，同时脂肪族环肽的荧光性能对非典型性荧光材料的体系是一种很好的补充。