Four of a kind: a complete collection of ADP-ribosylated histidine isosteres using Cu(I)- and Ru(II)-catalyzed click chemistry

Minnee, H.; Chung, H.W.; Rack, J.G.M.; Marel, G.A. van der; Overkleeft, H.S.; Codee, J.D.C.; ... ; Filippov, D.V. (2023)

Article / Letter to editor

Adenosine diphosphateribosylation (ADP-ribosylation) is a crucialpost-translational modification involved in important regulatory mechanismsof numerous cellular pathways including histone maintenance and DNAdamage repair. To study this modification, well-defined ADP-ribosylatedpeptides, proteins, and close analogues thereof have been invaluabletools. Recently, proteomics studies have revealed histidine residuesto be ADP-ribosylated. We describe here the synthesis of a completeset of triazole-isosteres of ADP-ribosylated histidine to serve asprobes for ADP-ribosylating biomachinery. By exploiting Cu(I)- andRu(II)-catalyzed click chemistry between a propargylglycine buildingblock and an & alpha;- or & beta;-configured azidoribose, we have successfullyassembled the & alpha;- and & beta;-configured 1,4- and 1,5-triazoles,mimicking N(& tau;)- and N(& pi;)-ADP-ribosylated histidine, respectively.The ribosylated building blocks could be incorporated into a peptidesequence using standard solid-phase peptide synthesis and transformedon resin into the ADP-ribosylated fragments to provide a total offour ADP-ribosyl triazole conjugates, which were evaluated for theirchemical and enzymatic stability. The 1,5-triazole analogues mimickingthe N(& pi;)-substituted histidines proved susceptible to base-inducedepimerization and the ADP-ribosyl & alpha;-1,5-triazole linkage couldbe cleaved by the (ADP-ribosyl)hydrolase ARH3.

• All authors: Minnee, H.; Chung, H.W.; Rack, J.G.M.; Marel, G.A. van der; Overkleeft, H.S.; Codee, J.D.C.; Ahel, I.; Filippov, D.V.
• Date: 2023-07-18
• Journal: Journal of Organic Chemistry (JOC)
• Volume: 88
• Issue: 15
• Pages: 10801 - 10809
• DOI: doi:10.1021/acs.joc.3c00827
• Link: https://pubs.acs.org/doi/10.1021/acs.joc.3c00827