Science of Synthesis

Gillingham, D.; Sauter, B., Science of Synthesis: DNA-Encoded Libraries, (2024) 1, 561.

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.

Me eeeeeee, eeeee eee eee eeeeeeeeee ee MMM-eeeee eeeeeeeeee eeeeee: eeeee ee eeee eeeeeeeeeeeeeeee (‌Meeeee 8‌). Me eeee, eeeeee eee eeeeeeeeeeeee eeee eeeeeee eee eeee eeeeeeeeeeeeeeee eeeeeeee, eeeee eeeeeee eeeeeeeee ee eeeeeeee ee eeeeee eeeeeeeee ee eee eeeeeeeee eeeeeeee, eee eee eeeeeeeeee ee eeeeeee ee eee eeeee (ee eeeeee eeeee) eeee (Meeeee 8e). M eeeeeeeeeeee ee eeee eeeeeeee ee eee eeeeeeeeeee eeee eeeeeeeeeeeeeeee eeee eeeee eee eee eeeeeee eeeeeee. Mee MMM MMM eee eee eeeeeeeeee ee eeeeeeeee eeeeeeee, eeeee e eeeeee eeeeeeeeee eeeeeee eeeee eeeeeeeeee eeeeeeee eeeeeee eee eeee-eeeee eeeeeeeee ee eeeee eee-MMM (Meeeee 8e).[‌8‌] Meee eeeeeeee, e eeeeeeeeeee eeee ee eeeeeee eeeeeee eeee eeee eeeeeee eeeeeee.[‌8‌] Mee eeeeeeeeee ee eeeeeeeee ee MMM eee eeeeeee eeeeeee e eeeee-eeeee eeeeeee eeeeeeeeeeee. Meee eeeeeeee eeeeeee eee eeeeeeeeeee ee eee eeeeeeeeeeeeeeee eeeeeeeee eee eeeeee eeeeeeee ee eeeeeee eeee eeeeee eee eeeeeee eeeeeeeee. Me eeeee eeee ee eeeeeeee eeeee eee eeeeeeeeee ee eeeeeeeeeee ee-MMM, eeeee eeeee ee e eeeeee ee eeeeeeeeee eeeeeeee eeeeeeeeeeee eee-MMM eeeeeeeeeeeeeeee eeeeeeeeee.[‌8‌,‌8‌]

‌Meeeee 8‌ Mee Meeeeeeeee eee MMM-Meeeeee Meeeeeeeee Meeeeeeee eeee Meeeeeeee Meeeee (MMe) Meeeeeeeee Meeeee Meeeeeeeeeeeeeee (e) ee Meeeeeeeee (e)

References