Glycinamide‐Driven Coumarin Construction (GDCC): A Mild Strategy for Fluorescent Labeling and Macrocyclization of Peptides
Abstract
ABSTRACT Peptidic macrocycles have attracted increasing attention due to their well‐defined structures and enhanced biological activities. However, efficient cyclization of residues lacking reactive side chains remains a significant challenge. Herein, we report a glycinamide‐driven coumarin construction (GDCC) reaction that enables the in situ formation of coumarin scaffolds via condensation between C ‐terminal glycine residues and salicylaldehyde analogs under mild, metal‐ and catalyst‐free conditions. While various salicylaldehyde derivatives afford efficient fluorescent labeling, symmetrical salicylaldehyde‐based linkers uniquely promote intramolecular bis ‐glycine cyclization, generating intrinsically fluorescent peptide macrocycles with tunable topology and hydrophobicity. Notably, the optimal peptide 64 exhibits photophysical properties comparable or even superior to those of the coumarin gold standard, 7‐(diethylamino)‐4‐methylcoumarin. The GDCC reaction displays broad substrate scope and excellent compatibility with both solid‐phase and solution‐phase peptide synthesis. Its potential in chemical biology is demonstrated by the streamlined construction of diverse fluorescent cyclic peptides, including RGD‐based probes for live‐cell imaging, peptide–drug conjugates for targeted doxorubicin delivery, and a panel of PD‐1/PD‐L1 interaction inhibitors with tunable activity.
Article Details
Authors (16)
Xiao‐Fei Gao
jiangxi Provincial Key Laboratory of Organic Functional Molecules, Institute of Organic Chemistry, College of Chemistry and Chemical Engineering Jiangxi Science and Technology Normal University Nanchang China
Wei Xiao
Center for Plant Molecular Biology, University of Tübingen
Tian‐Ming Tao
National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine Jiangxi University of Chinese Medicine Nanchang China
Feng‐Cai Ma
National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine Jiangxi University of Chinese Medicine Nanchang China
Xiao‐Yan Liu
jiangxi Provincial Key Laboratory of Organic Functional Molecules, Institute of Organic Chemistry, College of Chemistry and Chemical Engineering Jiangxi Science and Technology Normal University Nanchang China
Xue Jiang
Zhong‐Hong Liu
jiangxi Provincial Key Laboratory of Organic Functional Molecules, Institute of Organic Chemistry, College of Chemistry and Chemical Engineering Jiangxi Science and Technology Normal University Nanchang China
Xing‐Lei Zhang
Key Laboratory for Mass Spectrometry and Instrumentation East China University of Technology Nanchang China
Yu Chai
National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine
Emeric Miclet
Sorbonne Université, Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, 4 place Jussieu, Paris Cedex 05, 75252, France
Valérie Alezra
Laboratoire de Méthodologie, Synthèse et Molécules Thérapeutiques, ICMMO, Université Paris-Saclay
Yuan‐Biao Tu
National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine Jiangxi University of Chinese Medicine Nanchang China
Qi‐Dong Tu
jiangxi Provincial Key Laboratory of Organic Functional Molecules, Institute of Organic Chemistry, College of Chemistry and Chemical Engineering Jiangxi Science and Technology Normal University Nanchang China
Yang Wan
National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine
Hai‐Sheng Wang
jiangxi Provincial Key Laboratory of Organic Functional Molecules, Institute of Organic Chemistry, College of Chemistry and Chemical Engineering Jiangxi Science and Technology Normal University Nanchang China
Qiang Xiao