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

• Published in: Chemistry : a European journal 2017-10, Vol.23 (60), p.15227-15232
• Main 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
• Format: Article
• Language: English
• Subjects: ATPases Associated with Diverse Cellular Activities - chemistry; ATPases Associated with Diverse Cellular Activities - metabolism; Binding Sites; Biological Products - chemical synthesis; Biological Products - chemistry; Biological Products - metabolism; Catalytic Domain; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; High-Throughput Screening Assays; Histone Acetyltransferases; Histone Chaperones; Humans; Jumonji Domain-Containing Histone Demethylases - chemistry; Jumonji Domain-Containing Histone Demethylases - metabolism; Ligands; Molecular Docking Simulation; Nuclear Proteins - chemistry; Nuclear Proteins - metabolism; Protein Domains; Quantum Theory; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - metabolism
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201704169

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 -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.