Ramírez-López Pedro, Suárez José Ramón, Flores Aida, Hernáiz María J
Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, Plz. Ramón y Cajal s/n, Madrid, C.P. 28040, España.
Bioconjug Chem. 2025 Aug 20;36(8):1553-1581. doi: 10.1021/acs.bioconjchem.5c00049. Epub 2025 Jul 17.
Efficient and biocompatible methods for synthesizing glycoconjugates are essential in chemical biology, as these molecules play pivotal roles in cellular recognition, signaling, and immune responses. Abnormal glycosylation is associated with diseases such as cancer, infections, and immune disorders, positioning glycoconjugates as promising candidates for therapeutic, diagnostic, and drug delivery applications. Traditional chemical approaches often lack biocompatibility and efficiency; however, the advent of metal-free click chemistry has revolutionized glycoconjugate synthesis by providing selective and versatile tools under mild conditions. This review highlights four remarkable metal-free click reactions: thiol-ene coupling (TEC), strain-promoted azide-alkyne cycloaddition (SPAAC), inverse electron-demand Diels-Alder (IEDDA) reaction, and sulfur fluoride exchange (SuFEx). TEC enables the regio- and stereoselective synthesis of glycoconjugates, including S-polysaccharides, glycopeptides, and glycoclusters, advancing vaccine development and carbohydrate-based therapeutics. SPAAC, a bioorthogonal and metal-free alternative, facilitates imaging, glycan monitoring, the synthesis of glycofullerenes and glycovaccines, and the development of targeted protein degradation systems such as lysosome-targeting chimeras (LYTACs). Additionally, the combination of SPAAC with biocatalysis offers a sustainable approach for preparing glycoconjugates with therapeutic potential. The IEDDA reaction, a highly efficient metal-free biorthogonal cycloaddition, plays a key role in metabolic glycoengineering for live-cell imaging and glycan-based therapies and also contributes to the creation of injectable hydrogels for drug delivery and tissue engineering. SuFEx, a more recent reaction, enables efficient sulfonamide and sulfonate bond formation, broadening the toolbox for glycoconjugate and protein functionalization. These methodologies are transforming glycochemistry and glycobiology, driving advancements in biomedicine, materials science, and pharmaceutical development.
合成糖缀合物的高效且生物相容的方法在化学生物学中至关重要，因为这些分子在细胞识别、信号传导和免疫反应中起着关键作用。异常糖基化与癌症、感染和免疫紊乱等疾病相关，这使得糖缀合物成为治疗、诊断和药物递送应用的有前景的候选物。传统化学方法往往缺乏生物相容性和效率；然而，无金属点击化学的出现通过在温和条件下提供选择性和多功能工具，彻底改变了糖缀合物的合成。本综述重点介绍了四种显著的无金属点击反应：硫醇-烯偶联（TEC）、应变促进的叠氮化物-炔烃环加成（SPAAC）、逆电子需求狄尔斯-阿尔德（IEDDA）反应和硫氟交换（SuFEx）。TEC能够实现糖缀合物的区域和立体选择性合成，包括S-多糖、糖肽和糖簇，推动疫苗开发和基于碳水化合物的治疗。SPAAC是一种生物正交且无金属的替代方法，有助于成像、聚糖监测、糖富勒烯和糖疫苗的合成，以及靶向蛋白质降解系统如溶酶体靶向嵌合体（LYTACs）的开发。此外，SPAAC与生物催化的结合为制备具有治疗潜力的糖缀合物提供了一种可持续的方法。IEDDA反应是一种高效的无金属生物正交环加成反应，在用于活细胞成像和基于聚糖的治疗的代谢糖工程中起关键作用，也有助于创建用于药物递送和组织工程的可注射水凝胶。SuFEx是一种较新的反应，能够实现高效磺酰胺和磺酸酯键的形成，拓宽了糖缀合物和蛋白质功能化的工具库。这些方法正在改变糖化学和糖生物学，推动生物医学、材料科学和药物开发的进步。
