Karageorgis, G orcid.org/0000-0001-5088-6047, Dow, M, Aimon, A et al. (2 more authors) (2015) Activity-Directed Synthesis with Intermolecular Reactions: Development of a Fragment into a Range of Androgen Receptor Agonists. Angewandte Chemie International Edition, 54 (46). pp. 13538-13544. ISSN 1433-7851
Abstract
Activity-directed synthesis (ADS), a novel discovery approach in which bioactive molecules emerge in parallel with associated syntheses, was exploited to develop a weakly binding fragment into novel androgen receptor agonists. Harnessing promiscuous intermolecular reactions of carbenoid compounds enabled highly efficient exploration of chemical space. Four substrates were prepared, yet exploited in 326 reactions to explore diverse chemical space; guided by bioactivity alone, the products of just nine of the reactions were purified to reveal diverse novel agonists with up to 125-fold improved activity. Remarkably, one agonist stemmed from a novel enantioselective transformation; this is the first time that an asymmetric reaction has been discovered solely on the basis of the biological activity of the product. It was shown that ADS is a significant addition to the lead generation toolkit, enabling the efficient and rapid discovery of novel, yet synthetically accessible, bioactive chemotypes.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (C) 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | activity-directed synthesis; agonists; bioactive molecules; carbenoids; reaction discovery |
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: | 04 Nov 2015 11:59 |
Last Modified: | 14 May 2019 10:48 |
Published Version: | http://dx.doi.org/10.1002/anie.201506944 |
Status: | Published |
Publisher: | Wiley-VCH Verlag |
Identification Number: | 10.1002/anie.201506944 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:91456 |