Journal Article

Organometallic palladium reagents for cysteine bioconjugation

Zhang, Chi, Buchwald, Stephen L., Vinogradova, Ekaterina V., Pentelute, Bradley L., Spokoyny, Alexander M.

2015

Overview

Palladium( ii ) complexes can be used in efficient and highly selective cysteine conjugation reactions that are rapid and robust, and the resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. A new route to S -aryl conjugates These authors demonstrate that palladium( II ) complexes can be used in efficient and highly selective cysteine conjugation reactions that are rapid and robust, and the resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the new bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody–drug conjugates. Previously the use of transition-metal based reactions to modify complex biomolecules has proved problematic due mainly to the need for stringent reaction conditions and the presence of multiple reactive functional groups in peptides. Reactions based on transition metals have found wide use in organic synthesis, in particular for the functionalization of small molecules 1 , 2 . However, there are very few reports of using transition-metal-based reactions to modify complex biomolecules 3 , 4 , which is due to the need for stringent reaction conditions (for example, aqueous media, low temperature and mild pH) and the existence of multiple reactive functional groups found in biomolecules. Here we report that palladium( ii ) complexes can be used for efficient and highly selective cysteine conjugation (bioconjugation) reactions that are rapid and robust under a range of bio-compatible reaction conditions. The straightforward synthesis of the palladium reagents from diverse and easily accessible aryl halide and trifluoromethanesulfonate precursors makes the method highly practical, providing access to a large structural space for protein modification. The resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody–drug conjugates. These palladium complexes show potential as benchtop reagents for diverse bioconjugation applications.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/92/612 / 639/638/406 / Amino acids / Analysis / Catalysis / Chemical properties / Chemical reactions / Chemical tests and reagents / Chemistry Techniques, Synthetic / Cysteine / Cysteine - chemistry / Humanities and Social Sciences / Hydrogen-Ion Concentration / Indicators and Reagents / letter / Ligands / Low temperature / Molecular Structure / multidisciplinary / Organometallic Compounds - chemistry / Oxidizing agents / Palladium / Palladium - chemistry / Peptides / Pharmaceutical Preparations - chemistry / Proteins / Proteins - chemistry / Reagents / Science