Modular synthesis of clickable peptides via late-stage maleimidation on C(7)-H tryptophan.
Peng WangJiang LiuXiaomei ZhuKenry KenryZhengqing YanJiahui YanJitong JiangManlin FuJingyan GeQing ZhuYuguo ZhengPublished in: Nature communications (2023)
Cyclic peptides have attracted tremendous attention in the pharmaceutical industry owing to their excellent cell penetrability, stability, thermostability, and drug-like properties. However, the currently available facile methodologies for creating such peptides are rather limited. Herein, we report an efficient and direct peptide cyclization via rhodium(III)-catalyzed C(7)-H maleimidation. Notably, this catalytical system has excellent regioselectivity and high tolerance of functional groups which enable late-stage cyclization of peptides. This architecture of cyclic peptides exhibits higher bioactivity than its parent linear peptides. Moreover, the Trp-substituted maleimide displays excellent reactivity toward Michael addition, indicating its potential as a click functional group for applications in chemical biology and medicinal chemistry. As a proof of principle, RGD-GFLG-DOX, which is a peptide-drug-conjugate, is constructed and it displays a strong binding affinity and high antiproliferative activity toward integrin-αvβ 3 overexpressed cancer cell lines. The proposed strategy for rapid preparation of stapled peptides would be a robust tool for creating peptide-drug conjugates.