Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures

Chemical Science
Mateja Klika ŠkopićAndreas Brunschweiger

Abstract

Libraries of DNA-tagged compounds are a validated screening technology for drug discovery. They are synthesized through combinatorial iterations of alternated coding and preparative synthesis steps. Thus, large chemical space can be accessed for target-based screening. However, the need to preserve the functionality of the DNA tag severely restricts the choice of chemical methods for library synthesis. Acidic organocatalysts, transition metals, and oxidants furnish diverse drug-like structures from simple starting materials, but cause loss of genetic information by depurination. A hexathymidine oligonucleotide, called "hexT" allows the chemist utilizing these classes of catalysts to access a potentially broad variety of structures in the initial step of library synthesis. We exploited its catalyst tolerance to efficiently synthesize diverse substituted β-carbolines, pyrazolines, and pyrazoles from readily available starting materials as hexT conjugates by acid- and Au(i)-catalysis, respectively. The hexT conjugates were ligated to coding DNA sequences yielding encoded screening libraries inspired by drug structures.

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Citations

Jun 13, 2018·Biological Chemistry·Verena KunigAndreas Brunschweiger
Apr 24, 2018·FEBS Letters·Nicholas FavalliDario Neri
Jun 17, 2020·Angewandte Chemie·Verena B K KunigAndreas Brunschweiger
Apr 28, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Johannes OttlChristoph E Dumelin
Oct 6, 2017·Organic & Biomolecular Chemistry·Mateja Klika ŠkopićAndreas Brunschweiger
Sep 25, 2017·ChemMedChem·Daniel ProbstJean-Louis Reymond
May 22, 2019·Expert Opinion on Drug Discovery·Guixian ZhaoXiaoyu Li
Oct 13, 2020·Chemical Reviews·Patrick R Fitzgerald, Brian M Paegel
Jun 21, 2021·Bioorganic & Medicinal Chemistry·Isaline F S F CastanMichael J Waring
Jun 22, 2021·Angewandte Chemie·Marco PotowskiAndreas Brunschweiger
Mar 13, 2019·Organic Letters·Huang-Chi DuMartin M Matzuk
Apr 9, 2020·Journal of the American Chemical Society·Matthias V WestphalStuart L Schreiber
Oct 31, 2019·Organic Letters·Stefanie N GeigleAlexander L Satz
Jun 28, 2019·Journal of the American Chemical Society·M Klika ŠkopićA Brunschweiger
Jan 25, 2019·Organic Letters·Xuan WangXiaojie Lu
Sep 4, 2021·Bioorganic & Medicinal Chemistry Letters·Richard J FairChristopher D Hupp
Nov 18, 2021·The Journal of Organic Chemistry·Jessica S GrahamMichael J Waring

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Methods Mentioned

BETA
fluorescence
pull-down
PCR

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