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Synthesis and Demonstration of the Biological Relevance of sp 3 -rich Scaffolds Distantly Related to Natural Product Frameworks

DOI: 10.1002/chem.201704169 DOI Help

Authors: Daniel J. Foley (University of Leeds) , Philip G. E. Craven (University of Leeds) , Patrick Collins (Diamond Light Source) , Richard G. Doveston (University of Leeds) , Anthony Aimon (Diamond Light Source) , Romain Talon (Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford) , Ian Churcher (BenevolentBio) , Frank Von Delft (Diamond Light Source) , Stephen P. Marsden (University of Leeds) , Adam Nelson (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry - A European Journal , VOL 73

State: Published (Approved)
Published: October 2017

Open Access Open Access

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.

Journal Keywords: chemical biology; fragments; molecular diversity; natural products; proteins

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 09/10/2017 14:36


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