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DOI: 10.1055/sos-SD-241-00242

Xu, H.; Ma, P.; Yang, G.Science of Synthesis: DNA Encoded Librariesearly view.

General Introduction

Natural products are privileged compounds of natural evolution that are often rich in sp3 carbon atoms, bear multiple stereocenters, and have diverse skeletons. These features endow natural products with a broad spectrum of pharmacological activities.[‌1‌] As a consequence, natural products play a key role in the history of medical treatment and drug discovery.[‌2‌] Figure 1 illustrates the “late-stage” DNA-labeling reaction, a facile and efficient method for functionality-independent DNA-encoding of complex natural products to generate a natural-product-enriched DEL library (nDEL), in which the volatile bifunctional linker 1 [3-(2-azidoethyl)-3-methyl-3H-diazirine] is critical to high-throughput DNA annotation of natural products.[‌3‌,‌4‌] The diazirine moiety in 1 reacts with natural products in a site- and chemo- nonselective manner, while the azide moiety conjugates with alkyne-containing headpiece DNA 2 via copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC).[‌5‌] Since the diazirine and azide functionalities in linker 1 are orthogonal under the optimized reaction conditions, a one-pot, stepwise reaction procedure is possible for DNA annotation of natural products, which can be carried out in parallel in a 96-well microplate. In a typical synthesis, the individual natural product molecule is dissolved in an organic solvent and mixed with excess linker 1 in each well of a 96-well microplate. The annotation reaction is initiated and proceeds to completion by UV irradiation at 365 nm. Remaining linker 1 and/or its side products can be readily removed under vacuum. The resulting linker-labeled natural products, after liquid chromatography–mass spectrometry (LC-MS) validation, are conjugated with alkyne-containing headpiece DNA 2 via CuAAC reaction, followed by enzyme-catalyzed DNA barcoding in the same wells of the original reaction plate. The final DNA-annotated natural products in each well are pooled, and mixed into a DEL library (nDEL).

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