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DOI: 10.1055/sos-SD-241-00235

Gillingham, D.; Sauter, B.Science of Synthesis: DNA-Encoded Libraries, (20241561.

General Introduction

Given the incredible bounty of macrocyclic molecules that natural evolution has produced, one would think that macrocycles would be regularly seen in screening collections. This is not the case. Although macrocyclic molecules from nature are either directly used as drugs, or have inspired the design of new drugs, medicinal chemists typically do not explore macrocycles in early drug discovery. There are several reasons for this, but synthetic tractability is the one most germane for DNA-encoded library (DEL) practitioners. Macrocycles typically require complex syntheses that resist the compound analoging so essential for all stages of small-molecule drug development. The split-and-pool combinatorial synthesis technique is ideally suited for creating large libraries with minimal synthesis effort. Particularly in the case of macrocycles, using split-and-pool DELs has enabled an enormous extension to the chemical space of synthetic macrocycles. Nevertheless, even DEL-based macrocycle libraries are limited by synthesis complexity, which has been summarized in a recent review.[‌1‌] Here, we discuss synthesis strategies and experimental details for the validated strategies of macrocycle synthesis on DNA.

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