We report a chemoselective and site-selective approach that distinguishes one Lys from its multiple copies, N-terminus, and other competitors. The phospha-Mannich protocol works with multiple proteins and installs probes without structural and functional perturbations. It delivers an antibody-drug conjugate with selective anti-proliferative activity towards HER2 expressing SKBR3 breast cancer cells.

Carbon-centered radicals are indispensable building blocks for modern synthetic chemistry. In recent years, visible light photoredox catalysis has become a promising avenue to access C-centered radicals from a broad array of latent functional groups, including boronic acids. Herein, we present an aqueous protocol wherein water features a starring role to help transform aliphatic, aromatic, and heteroaromatic boronic acids to C-centered radicals with a bioinspired flavin photocatalyst. These radicals are used to deliver a diverse pool of alkylated products, including three pharmaceutically relevant compounds, via open-shell conjugate addition to disparate Michael acceptors. The mechanism of the reaction is investigated by computational studies, deuterium labeling, radical-trapping experiments, and spectroscopic analysis.

Chemical functionalization of proteins is an indispensable tool. Yet, selective labeling of native proteins has been an arduous task. The limited success of chemical methods allows N-terminus protein labeling, but the examples with side-chain residues are rare. Herein, we surpass this challenge through a multicomponent transformation that operates under physiological conditions in the presence of a protein, aldehyde, acetylene, and Cu-ligand complex. The methodology results in the labeling of a single lysine residue in nine distinct proteins.

Most peptide drugs contain non-proteinogenic amino acids (NPAAs), born out through extensive structure-activity relationship (SAR) studies using solid-phase peptide synthesis (SPPS). Synthetically laborious and expensive to manufacture, NPAAs also can...