Synthesis and Demonstration of the Biological Relevance of sp3‐rich Scaffolds Distantly Related to Natural Product Frameworks. Issue 60 (6th October 2017)

• Record Type: Journal Article
• Authors: Foley, Daniel J.; Craven, Philip G. E.; Collins, Patrick M.; Doveston, Richard G.; Aimon, Anthony; Talon, Romain; Churcher, Ian; von Delft, Frank; Marsden, Stephen P.; Nelson, Adam
• Is Part Of: Chemistry. Volume 23:Issue 60(2017)
• Page Start: 15227
• Page End: 15232
• Publication Date: 2017-10-06
• Subjects: chemical biology -- fragments -- molecular diversity -- natural products -- proteins; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201704169
• Languages: English
• ISSNs: 0947-6539

Abstract

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 sp 3 ‐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. Abstract : A "top‐down" approach enabled preparation of diverse scaffolds with local natural product‐like features, but that are only distantly related to specific natural product frameworks. A fragment set based on many of the scaffolds was screened by high‐throughput crystallography against three targets (ATAD2, BRD1, JMJD2D) yielding, in each case, distinctive fragment hits. Frameworks distantly related to natural products can thus facilitate discovery of new biologically relevant regions of chemical space.