Chemical modification of proteins and peptides represents a challenge of reaction design as well as an important biological tool. In contrast to side-chain modification, synthetic methods to alter backbone structure are extremely limited. In this communication, copper-mediated backbone N-alkenylation or N-arylation of peptides and proteins by direct modification of natural sequences is described. Histidine residues direct oxidative coupling of boronic acids at the backbone NH of a neighboring amino acid. The mild reaction conditions in common physiological buffers, at ambient temperature, are compatible with proteins and biological systems. This simple reaction demonstrates the potential for directed reactions in complex systems to allow modification of N-H bonds that directly affect polypeptide structure, stability, and function.

Nearly 40% of children with acute myeloid leukemia (AML) suffer relapse due to chemoresistance, often involving upregulation of the oncoprotein STAT3 (signal transducer and activator of transcription 3). In this paper, rhodium(II)-catalyzed, proximity-driven modification identifies the STAT3 coiled-coil domain (CCD) as a novel ligand-binding site, and we describe a new naphthalene sulfonamide inhibitor that targets the CCD, blocks STAT3 function, and halts its disease-promoting effects in vitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML.

Rhodium(II)–fluorophore conjugates have strong rhodium-based fluorescence quenching that can be harnessed to report on a conjugate’s cellular uptake and the intracellular decomposition rate. Information gleened from this study allowed the design of an improved STAT3 metalloinhibitor.

The use of parallel synthesis protocols for asymmetric reaction discovery has increased the need for new methods to rapidly determine enantiomeric excess (ee) values. Most chirality sensing is performed on stereocenters that are a (i.e., proximal) to the target functional group. Herein, we demonstrate a design principle to ''reach out'' to more distant stereocenters. Therefore, we see the design principles established in this work as a step forward in sensing distant point chirality and, eventually, multi-stereocenter relationships.