Late-Stage Functionalization of Histidine in Unprotected Peptides.

Autor: Noisier AFM; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceutical R&D, AstraZeneca, Gothenburg, Sweden., Johansson MJ; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceutical R&D, AstraZeneca, Gothenburg, Sweden., Knerr L; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceutical R&D, AstraZeneca, Gothenburg, Sweden., Hayes MA; Discovery Sciences, BioPharmaceutical R&D, AstraZeneca, Gothenburg, Sweden., Drury WJ 3rd; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceutical R&D, AstraZeneca, Gothenburg, Sweden., Valeur E; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceutical R&D, AstraZeneca, Gothenburg, Sweden., Malins LR; Research School of Chemistry, Australian National University, Acton, ACT 2601, Australia., Gopalakrishnan R; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceutical R&D, AstraZeneca, Gothenburg, Sweden.; Medicinal Chemistry, Research and Early Development Respiratory, Inflammation and Autoimmune, BioPharmaceutical R&D, AstraZeneca, Gothenburg, Sweden.; AstraZeneca MPI Satellite Unit, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2019 Dec 19; Vol. 58 (52), pp. 19096-19102. Date of Electronic Publication: 2019 Nov 07.
DOI: 10.1002/anie.201910888
Abstrakt: The late-stage functionalization (LSF) of peptides represents a valuable strategy for the design of potent peptide pharmaceuticals by enabling rapid exploration of chemical diversity and offering novel opportunities for peptide conjugation. While the C(sp 2 )-H activation of tryptophan (Trp) is well documented, the resurgence of radical chemistry is opening new avenues for the C-H functionalization of other aromatic side-chains. Herein, we report the first example of LSF at C2 of histidine (His) utilizing a broad scope of aliphatic sulfinate salts as radical precursors. In this work, the exquisite selectivity for histidine functionalization was demonstrated through the alkylation of complex unprotected peptides in aqueous media. Finally, this methodology was extended for the installation of a ketone handle, providing an unprecedented anchor for selective oxime/hydrazone conjugation at histidine.
(© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
Externí odkaz: