Synthesis of a DNA-Encoded Macrocyclic Library Utilizing Intramolecular Benzimidazole Formation

Macrocycles occupy chemical space beyond therule of five.They bridge traditional bioactive small molecule drugs and macromoleculesand have the potential to modulate challenging targets such as PPIor proteases. Here we report an on-DNA macrocyclization reaction utilizingintramolecular benzimidazole formation. A 129-million-member macrocycliclibrary composed of a privileged benzimidazole core, a dipeptide sequence(natural or non-natural), and linkers of varying length and flexibilitywas designed and synthesized.

Automated summary

Macrocycles expand chemical space beyond the rule of five and have the potential to modulate challenging targets. We report a DNA-based macrocyclization reaction using intramolecular benzimidazole formation. A 129-million-member macrocyclic library with a benzimidazole core, dipeptide sequence, and varying linkers was designed and synthesized.