{"doi":"10.1021/jacs.3c00210","title":"Chemoselective, Oxidation-Induced Macrocyclization of Tyrosine-Containing Peptides","abstract":"Inspired by nature's wide range of oxidation-induced modifications to install cross-links and cycles at tyrosine (Tyr) and other phenol-containing residue side chains, we report a Tyr-selective strategy for the preparation of Tyr-linked cyclic peptides. This approach leverages N4-substituted 1,2,4-triazoline-3,5-diones (TADs) as azo electrophiles that react chemoselectively with the phenolic side chain of Tyr residues to form stable C-N1-linked cyclic peptides. In the developed method, a precursor 1,2,4-triazolidine-3,5-dione moiety, also known as urazole, is readily constructed at any free amine revealed on a solid-supported peptide. Once prepared, the N4-substituted urazole peptide is selectively oxidized using mild, peptide-compatible conditions to generate an electrophilic N4-substituted TAD peptide intermediate that reacts selectively under aqueous conditions with internal and terminal Tyr residues to furnish Tyr-linked cyclic peptides. The approach demonstrates good tolerance of native residue side chains and enables access to cyclic peptides ranging from 3- to 11-residues in size (16- to 38-atom-containing cycles). The identity of the installed Tyr-linkage, a stable covalent C-N1 bond, was characterized using NMR spectroscopy. Finally, we applied the developed method to prepare biologically active Tyr-linked cyclic peptides bearing the integrin-binding RGDf epitope.","journal":"Journal of the American Chemical Society","year":2023,"id":327255,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1047349,"name":"Marcus C. Mifflin","orcid":"0000-0002-5283-9663","position":1,"is_corresponding":false},{"id":1048017,"name":"Maxwell J. Austin","orcid":null,"position":2,"is_corresponding":false},{"id":1048018,"name":"Brighton J. Alvey","orcid":null,"position":3,"is_corresponding":false},{"id":1048019,"name":"Lotfa H. Lovely","orcid":null,"position":4,"is_corresponding":false},{"id":1048020,"name":"Andriea Smith","orcid":null,"position":5,"is_corresponding":false},{"id":1048021,"name":"Tristin E. Rose","orcid":null,"position":6,"is_corresponding":false},{"id":685056,"name":"Bethany A. Buck‐Koehntop","orcid":"0000-0003-2421-7012","position":7,"is_corresponding":false},{"id":1047350,"name":"Jyoti Motwani","orcid":"0000-0001-5943-5373","position":8,"is_corresponding":false},{"id":454711,"name":"Andrew G. Roberts","orcid":"0000-0002-2221-534X","position":9,"is_corresponding":false},{"id":729628,"name":"E. Dalles Keyes","orcid":"0000-0002-1495-5890","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T01:08:42.846627Z","pmid":"37119237","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}