Synthesis of DNA-Encoded Macrocyclic Peptides via Visible-Light-Mediated Desulfurative C-C Bond Formation.

DNA-encoded library (DEL) technology has been developed to serve as a practical platform for the discovery of biologically active macrocyclic peptide compounds. However, the cyclization of linear peptides has been widely regarded as the challenging step in the production of macrocyclic peptide DELs. Herein, we describe a novel DNA-compatible macrocyclization strategy, which enables the construction of ring systems via visible-light-mediated desulfurative C-C bond formation.

Discovery, Characterization, and Structure of a Cell Active PAD2 Inhibitor Acting through a Novel Allosteric Mechanism.

Peptidyl arginine deiminases (PADs) are important enzymes in many diseases, especially those involving inflammation and autoimmunity. Despite many years of effort, developing isoform-specific inhibitors has been a challenge. We describe herein the discovery of a potent, noncovalent PAD2 inhibitor, with selectivity over PAD3 and PAD4, from a DNA-encoded library.

Photoredox Deaminative Alkylation in DNA-Encoded Library Synthesis.

Herein, we report an on-DNA photoredox-mediated deaminative alkylation method for diversifying DNA-tagged acrylamide substrate with amine-derived radicals. The radicals can be conveniently generated from sterically hindered primary amines, and the deaminative alkylation can tolerate a broad array of radical precursors. Furthermore, the methodology is applicable to Boc-protected diamines, free amino acids, and aryl halides, which bear functional groups enabling additional rounds of diversification.

On-DNA Derivatization of Quinoxalin-2-ones by Visible-Light-Triggered Alkylation with Carboxylic Acids.

An efficient visible-light-induced alkylation of DNA-tagged quinoxaline-2-ones was described. The methodology demonstrated moderate-to-excellent conversions under mild conditions. The reaction was found to be tolerant with both -protected α-amino acids and aliphatic carboxylic acids and could be applied to the synthesis of focused DNA-encoded quinoxalin-2-one libraries.

Functionalization of DNA-Tagged Alkenes Enabled by Visible-Light-Induced C-H Activation of -Aryl Tertiary Amines.

A highly efficient approach to C(sp)-C(sp) bond construction via on-DNA photoredox catalysis between on-DNA alkenes and -aryl tertiary amines was developed. The methodology demonstrated 55%-95% conversions without obvious DNA damage, as seen by qPCR tests. Furthermore, various functional groups, such as carboxylic acids, aldehydes, and aryl halides, that can be used to create library diversities were shown to be tolerant of the C-H activation conditions.