Karageorgis, G orcid.org/0000-0001-5088-6047, Warriner, S orcid.org/0000-0002-7589-6011 and Nelson, A orcid.org/0000-0003-3886-363X (2014) Efficient discovery of bioactive scaffolds by activity-directed synthesis. Nature Chemistry, 6 (10). pp. 872-876. ISSN 1755-4330
Abstract
The structures and biological activities of natural products have often provided inspiration in drug discovery. The functional benefits of natural products to the host organism steers the evolution of their biosynthetic pathways. Here, we describe a discovery approach-which we term activity-directed synthesis-in which reactions with alternative outcomes are steered towards functional products. Arrays of catalysed reactions of α-diazo amides, whose outcome was critically dependent on the specific conditions used, were performed. The products were assayed at increasingly low concentration, with the results informing the design of a subsequent reaction array. Finally, promising reactions were scaled up and, after purification, submicromolar ligands based on two scaffolds with no previous annotated activity against the androgen receptor were discovered. The approach enables the discovery, in tandem, of both bioactive small molecules and associated synthetic routes, analogous to the evolution of biosynthetic pathways to yield natural products.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2014, by the authors . This is an author produced version of a paper published in Nature Chemistry. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 21 Oct 2014 12:04 |
Last Modified: | 03 Dec 2020 11:20 |
Published Version: | http://dx.doi.org/10.1038/nchem.2034 |
Status: | Published |
Publisher: | Nature Publishing Group |
Refereed: | Yes |
Identification Number: | 10.1038/nchem.2034 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:80660 |