ArticleAngewandte Chemie (International ed. in English)2015
Activity-Directed Synthesis with Intermolecular Reactions: Development of a Fragment into a Range of Androgen Receptor Agonists.
Article in Angewandte Chemie (International ed. in English), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Direct-to-Biology: Streamlining the Path From Chemistry to Biology in Drug Discovery.ChemMedChem · 2026Review
- Toward target 2035: EUbOPEN - a public-private partnership to enable & unlock biology in the open.RSC medicinal chemistry · 2025Article
- Synthesis of 2,6-Organic letters · 2024Article
- Natural product-informed exploration of chemical space to enable bioactive molecular discovery.RSC medicinal chemistry · 2021Review
- Computational Mapping of Dirhodium(II) Catalysts.Chemistry (Weinheim an der Bergstrasse, Germany) · 2021Article
- Activity-Directed Synthesis: A Flexible Approach for Lead Generation.ChemMedChem · 2020Article
- Activity-Directed Synthesis of Inhibitors of the p53/hDM2 Protein-Protein Interaction.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
- Expanding the medicinal chemistry synthetic toolbox.Nature reviews. Drug discovery · 2018Review
- Nanoscale synthesis and affinity ranking.Nature · 2018Article
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Authors and funding
5 authors.
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Abstract
Activity-directed synthesis (ADS), a novel discovery approach in which bioactive molecules emerge in parallel with associated syntheses, was exploited to develop a weakly binding fragment into novel androgen receptor agonists. Harnessing promiscuous intermolecular reactions of carbenoid compounds enabled highly efficient exploration of chemical space. Four substrates were prepared, yet exploited in 326 reactions to explore diverse chemical space; guided by bioactivity alone, the products of just nine of the reactions were purified to reveal diverse novel agonists with up to 125-fold improved activity. Remarkably, one agonist stemmed from a novel enantioselective transformation; this is the first time that an asymmetric reaction has been discovered solely on the basis of the biological activity of the product. It was shown that ADS is a significant addition to the lead generation toolkit, enabling the efficient and rapid discovery of novel, yet synthetically accessible, bioactive chemotypes.
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