Bio-Organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden 2300 RA, The Netherlands.
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, U.K.
J Org Chem. 2023 Aug 4;88(15):10801-10809. doi: 10.1021/acs.joc.3c00827. Epub 2023 Jul 18.
Adenosine diphosphate ribosylation (ADP-ribosylation) is a crucial post-translational modification involved in important regulatory mechanisms of numerous cellular pathways including histone maintenance and DNA damage repair. To study this modification, well-defined ADP-ribosylated peptides, proteins, and close analogues thereof have been invaluable tools. Recently, proteomics studies have revealed histidine residues to be ADP-ribosylated. We describe here the synthesis of a complete set of triazole-isosteres of ADP-ribosylated histidine to serve as probes for ADP-ribosylating biomachinery. By exploiting Cu(I)- and Ru(II)-catalyzed click chemistry between a propargylglycine building block and an α- or β-configured azidoribose, we have successfully assembled the α- and β-configured 1,4- and 1,5-triazoles, mimicking N(τ)- and N(π)-ADP-ribosylated histidine, respectively. The ribosylated building blocks could be incorporated into a peptide sequence using standard solid-phase peptide synthesis and transformed on resin into the ADP-ribosylated fragments to provide a total of four ADP-ribosyl triazole conjugates, which were evaluated for their chemical and enzymatic stability. The 1,5-triazole analogues mimicking the N(π)-substituted histidines proved susceptible to base-induced epimerization and the ADP-ribosyl α-1,5-triazole linkage could be cleaved by the (ADP-ribosyl)hydrolase ARH3.
二磷酸腺苷核糖基化 (ADP-ribosylation) 是一种重要的翻译后修饰，参与许多细胞途径的重要调节机制，包括组蛋白维持和 DNA 损伤修复。为了研究这种修饰，定义明确的 ADP-ribosylated 肽、蛋白质及其密切类似物是非常有价值的工具。最近，蛋白质组学研究表明组氨酸残基被 ADP-ribosylated。我们在这里描述了一组完整的 ADP-ribosylated 组氨酸的三唑类似物的合成，作为 ADP-ribosylating 生物机器的探针。通过利用 Cu(I) 和 Ru(II) 催化的炔丙氨酸砌块与 α-或 β-构型的叠氮核糖之间的点击化学反应，我们成功地组装了模拟 N(τ)-和 N(π)-ADP-ribosylated 组氨酸的 α-和 β-构型的 1,4-和 1,5-三唑。通过标准固相肽合成，可以将核糖基砌块掺入肽序列中，并在树脂上转化为 ADP-ribosylated 片段，提供总共四种 ADP-ribosyl 三唑缀合物，对其进行了化学和酶稳定性评估。模拟 N(π)-取代组氨酸的 1,5-三唑类似物易受碱诱导的差向异构化影响，并且 ADP-ribosyl α-1,5-三唑键可以被 (ADP-ribosyl) 水解酶 ARH3 切割。
