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Efficient discovery of bioactive scaffolds by activity-directed synthesis


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.

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Figure 1: Application of activity-directed synthesis to the discovery of androgen receptor agonists.
Figure 2: Activity of product mixtures derived from reaction arrays.
Figure 3: Dose-dependent agonism of the androgen receptor by compounds 17, 18 and 19.
Figure 4: A selection of the alternative products accessible from α-diazo amides 8, 3 and 13, which were explored in rounds one, two and three.


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The authors acknowledge funding from the University of Leeds and from the EPSRC (for equipment). The authors also thank K. Krishenbaum, P. M. Levine (both New York University) and S. Bartlett (University of Leeds) for discussions.

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Authors and Affiliations



A.N. and S.W. conceived, designed and supervised the project. G.K. undertook the experimental work. A.N., S.W. and G.K. analysed the results and wrote the paper.

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Correspondence to Stuart Warriner or Adam Nelson.

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The authors declare no competing financial interests.

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Karageorgis, G., Warriner, S. & Nelson, A. Efficient discovery of bioactive scaffolds by activity-directed synthesis. Nature Chem 6, 872–876 (2014).

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