Premium
Synthesis and Demonstration of the Biological Relevance of sp 3 ‐rich Scaffolds Distantly Related to Natural Product Frameworks
Author(s) -
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
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201704169
Subject(s) - chemical space , natural product , drug discovery , relevance (law) , chemical biology , natural (archaeology) , computational biology , product (mathematics) , chemistry , combinatorial chemistry , biology , stereochemistry , biochemistry , paleontology , geometry , mathematics , political science , law
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.