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High fidelity Suzuki−Miyaura coupling for the synthesis of DNA encoded libraries enabled by micelle forming surfactants

Lookup NU author(s): James Hunter, Dr Lisa Prendergast, Professor Mike Waring

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Chemical Society, 2020.

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Abstract

DNA encoded chemical libraries provide a highly efficient means of screening vast numbers of small molecules against an immobilized protein target. Their potential is currently restricted by the constraints of carrying out library synthesis 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 Suzuki−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 two-dimensional 36-member library employing the Suzuki−Miyaura coupling methodology as the final library synthesis step. This work shows, for the first time, that standard micellar surfactants can promote reactions for encoded library synthesis, leading to libraries of exceptional fidelity, and demonstrates the potential to expand the range of accessible DNA compatible chemistry.


Publication metadata

Author(s): Hunter JH, Prendergast L, Valente LF, Madin A, Pairaudeau G, Waring MJ

Publication type: Article

Publication status: Published

Journal: Bioconjugate Chemistry

Year: 2020

Volume: 31

Issue: 1

Pages: 149-155

Print publication date: 15/01/2020

Online publication date: 24/12/2019

Acceptance date: 24/12/2019

Date deposited: 07/01/2020

ISSN (print): 1043-1802

ISSN (electronic): 1520-4812

Publisher: American Chemical Society

URL: https://doi.org/10.1021/acs.bioconjchem.9b00838

DOI: 10.1021/acs.bioconjchem.9b00838


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