James H. Hunter; Lisa Prendergast; Louis F. Valente; Andrew Madin; Garry Pairaudeau; Michael J. Waring
Bioconjugate Chem., 2020, 31, 1, 149-155
https://doi.org/10.1021/acs.bioconjchem.9b00838

Abstract

DNA encoded chemical libraries provide a highly efficient means of screening vast numbers of small molecules against an immobilised protein target. Their potential is currently restricted by the constraints of carrying out library synthe-sis in the presence of attached DNA tags, for which a limited number of reactions and substrates can be used. Even established reactions, such as Suzuki-Miyaura couplings, do not give efficient coupling reactions across a wide range of substrates and can lead to significant DNA degradation. We developed an efficient protocol for carrying out Suzu-ki-Miyaura couplings on DNA tagged substrates that proceeds with unprecedented efficiency to the desired biaryl products (>98% on average with no detectable DNA degradation) across a wide range of drug-like substrates using a micellar promoted process with commercial TPGS-750-M surfactant. We have demonstrated the applicability of this method in DEL synthesis by preparing a prototypical 2-dimensional 36-membered library employing the Suzuki-Miyaura coupling methodology as the final library synthesis step. This work shows, for the first time, that standard micellar surfactants enable reactions for encoded library synthesis, leading to libraries of exceptional fidelity, and demonstrates the potential to expand the range of accessible DNA compatible chemistry.