Foley, DJ, Craven, PGE orcid.org/0000-0002-7617-132X, Collins, PM et al. (7 more authors) (2017) Synthesis and Demonstration of the Biological Relevance of sp3-rich Scaffolds Distantly Related to Natural Product Frameworks. Chemistry - A European Journal, 23 (60). pp. 15227-15232. ISSN 0947-6539
Abstract
The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A “top-down” synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3-rich scaffolds. The scaffolds have local natural product-like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high-throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 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: | chemical biology; fragments; molecular diversity; natural products; proteins |
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: | 08 Sep 2017 08:52 |
Last Modified: | 23 Jun 2023 22:35 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/chem.201704169 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:121001 |