title: Efficient discovery of bioactive scaffolds by activity-directed synthesis.
abstract: The structures and biological activities of natural products have often provided inspiration in drug discovery. The functional benefits of natural products to the host organism steers the evolution of their biosynthetic pathways. Here, we describe a discovery approach--which we term activity-directed synthesis--in which reactions with alternative outcomes are steered towards functional products. Arrays of catalysed reactions of α-diazo amides, whose outcome was critically dependent on the specific conditions used, were performed. The products were assayed at increasingly low concentration, with the results informing the design of a subsequent reaction array. Finally, promising reactions were scaled up and, after purification, submicromolar ligands based on two scaffolds with no previous annotated activity against the androgen receptor were discovered. The approach enables the discovery, in tandem, of both bioactive small molecules and associated synthetic routes, analogous to the evolution of biosynthetic pathways to yield natural products.
authors.affiliation: 1] Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK [2] School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: George
authors.initials: G
authors.lastname: Karageorgis
authors.affiliation: 1] Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK [2] School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Warriner
authors.affiliation: 1] Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK [2] School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Nelson
mesh_terms: D000577:Amides / Q000737:chemistry; D000728:Androgens / Q000138:chemical synthesis; D001391:Azo Compounds / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis*; D002384:Catalysis; D055808:Drug Discovery; D007769:Lactams / Q000737:chemistry / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism
chemical_list: D000577:Amides; D000728:Androgens; D001391:Azo Compounds; D001688:Biological Products; D007769:Lactams; D011944:Receptors, Androgen