Science of Synthesis

Granados, A.; Molander, G. A., Science of Synthesis: DNA-Encoded Libraries, (2024) 1, 269.

General Introduction

DNA-encoded library (DEL) technologies have convincingly been demonstrated to have a tremendous capacity for the rapid discovery of therapeutic candidates in pharmaceutical environments.[‌1‌,‌2‌] This technology encompasses the synthesis and binding affinity of billions of organic molecules against a biological target in a single experiment, saving time and costs over those associated with traditional drug-discovery efforts. However, the presence of DNA imposes restrictions on the type of chemical transformations that are amenable within DEL environments.[‌3‌] These limitations include the need to conduct reactions under mild, dilute, and aqueous conditions. In particular, strong Brønsted/Lewis acids, high temperatures, oxidizing reagents, and chemical transformations requiring inert and/or dry conditions are impediments for practical implementation in high-performance environments from a synthetic point of view. To build structurally diverse DNA-encoded libraries, several chemical transformations have been adapted to maintain the limited chemical stability of the DNA tag against harsh reaction conditions. Among the reactions that have been implemented on-DNA, C—N cross-coupling reactions (Section 2.4),[‌4‌] palladium-catalyzed reactions (Section 2.2),[‌5‌] and ruthenium-promoted C—H activation (Section 2.5)[‌6‌] are prominent. Nevertheless, these methods typically require the use of high temperatures or harsh reagents. With the limitations presented above and with the aim to develop more benign methods for DEL synthesis, photoredox-catalyzed methods have enabled on-DNA transformations using photocatalysts or electron donor–acceptor strategies that harness visible light to build challenging organic structures.[‌1‌,‌2‌]

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‌Meeeee 8‌ Meeeeee Meeeeeeeeeeeee Meeee: Meeeeeeee Meeeeeeee eee Meeeeeeee Meeeeeeee Meeeeeee

Mee eeeeeeeeee ee eeee eeeeee eeeeeeeeeeeeee eee eeeeeeeee ee ‌Meeeee 8‌. Meeee eee eeeeee eeeeeeeee ee eee eeeeeeeeeee ee eeeeeeeeee eeeeeeeee ee eeeeeee eeeeeeeee, eeeeeeeeee-eeeee eeeeeeeee {e.e., Me(eee)8, Me(eeee)8(MM8)8, [Me{eM(MM8)eee}8(eeeeee)]MM8} eeee eeee eeee eeeeeeee eeee ee eeeeeeeeeeeeee. Meee ee, eee eeeeeeee ee eeeeeeeeeeeeee, eeee ee eeeeeeeeeeeeee eeeeeeeee (eeee ee eeeeeeeeeeeee) ee eeeeeee eeee (e.e., 8MeMMM), eee eeeeeeeeee ee ee eeeeeeee, eeeeeee eee eeeeeeeeeee eee eee eeeee ee eeeeeeee. Meeeeeee eeeeeee eeeeeeeeeeeeee eeeeeee eeeeeee eeeee eeeee eeeeeeeeee eee eeeeeee eeeeeee-eeeee eeeeeeeee, eee eeeeeeeeeee ee eeeee eeeeeeeeee ee e eeeeeeee eeee ee eeee eeeee eeeee eee eeeeeeeeeeeee eeeeeeeeee, eeee eeeeeee e eeeee eeeee ee eeeeeeeeeeeee ee eeeeeee eeeeeeeee.

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Me eeeeeeee eeeee, eee eeeeeeeeeee ee eeeeeeeee eeeeeeee eeeeeeeeeeeeeee ee-MMM eeeeeeee eeee, eeeeeee, eee eeeeee eeeeeeeeee. Me eeee eeeeee, eeeeeeeeee eeeeeeeee ee eeeeeee eeeeee. Meeee eee eeeee eeeeeeeeee eeeeeeeee ee-MMM, eeeee eee eeeeeeeee ee ee-MMM eeeeee ee ee-MMM eeeeee eeeee [Me(eeee)8]Me8 ee eee eeeeeeee ee eeeeeeeee eeeee e 88-M eeeeeee eeeeeeeeeee eeee (MMM) eeee eeeeeee eee,[‌88‌] eeee eeeee eeeeeeeeee eeee eeee eeeeeeeee. Meeeeeee eeeee eee eeeeee eeeeeeeeee eeeeeeeee eeeeeeeee e eeeeeeeeeeeee, ee eeeeeeeeeee eeeeeee eeeeeeeee, eee e eeeeeeee eeeeeeeeeee eeeeeeeee. Meeee-eeee eeeeeeee ee eeeeeeee, eeeeeeeee eeeeeeee ee e eeeeeee/eeeee eeeeeeeee eeeeeeeee, eee eeeeeeeeeeeee eeeeeeeee eee eeeeeeeee.

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‌Meeeee 8‌ Mee-Meeeeee Meeeee/Meeeeeeeee Meee Meeeeeeee Meeee[‌88‌]

MMM Meeeeee Meeeeee

Me eeeeeeeeeee eeeeeeee eeee eeeeeeeeeee eee eeee eee ee eeeeeeeee eeeeeeeeee eeeeeeee eeeeeeee eee eeeeeeeeeee ee eeeeeeee-eeeee/eeeeeeee-eeeeeeee eeeee (MMM eeeeeeeee) ee eeee eee eeeeeeeee eeeeeeeeee ee eee eeeeee eeeee (‌Meeeee 8‌). Meeeeeeee, eeeee MMM eeeeeeeee eeeeee eeeeee eeeeee eee eeeeeee-eeeee eeeeee ee eee eeeeeeee (888–888 ee). Meee, eeeeee eeeeeeeeeeeeeee eeeee eeeeeee eeeee eeeeeee ee eeeeeeeeeeeeee MMM eeeee (eeeeeeeeeeee eeeeeeee eeeeeeee), eeeeeeeeee e eeeeeee eee eeee, eeeee eee eeeeeeee eeee eee eeeeeeee eeeee ee eeeeeeeeeee ee eee eeeeeeee eeeeeeee.[‌88‌] Me eeeeeeee eee eeee-eeeeeeee-eeeeeeee eeeee eeee eeeee eeeee, eeee eeeeeeeee eee eeeeeee eeeeeeeee eeeeeeeee, eee eeeeeeee eeeeeeee eeeeeeeee eeeeeee e eeeeeeee eeeeeee eeeee (MM), eeeeeeee eeeeeeeeeeee eeeeeeeeeee ee eeeeee eeeeee ee eeeee eeee eeeeeeee eeee eeeeeeeeee eeeeeee eeeeeeeee. Mee eeeeeeeeeeeeeee ee eeeeeee eeeeeeeeeeeeeee eeeeeee ee MMM eeeeeeeee eeeee eeeeeeeeee-eeeee-eeee eeeeeeeeee ee e eeee eeeeeeee, eee eee eeee eeee eee eeee eeeeeeeeeeee.[‌88‌,‌88‌] Meeee eee eeeeeee eeeeeeeeee, eeee eeeeeeeeeeee eeeeeeee eee eeee eeee eeeeeeeeeeee eeeeeee ee MMM eeeeeeeeee.

‌Meeeee 8‌ Meeeeee Meeeeeeee ee eee MMM Meeeeee Meeeeeee[‌88‌]

MMMMMM: Me eeeeeee, eee eeeeeeee eeeeeeeee eeeeee ee eee eeeeeee eee eeeeeee eeeeeeee eeeeeeeeee. Meeeeee, eeeeee eee eeeeeee eeeeee ee eeeeeee eeee eeeeeeeeeee eeee eee eeeee-eeeeeeee eeeeee (MMMe) eeee eee eeeeeee-eeeee eeeeeeeeeee. Me eeee eeeee, eeee MMMe eee eeee eee eee ee eeeeeeeeeee eeeeeeee eeeee eeeeeeeeeeee eeeeeeeee, eeeeee-eeeeee eeeeee eeeeeee.

References