Activity‐Directed Synthesis with Intermolecular Reactions: Development of a Fragment into a Range of Androgen Receptor Agonists. Issue 46 (11th September 2015)

• Record Type: Journal Article
• Authors: Karageorgis, George; Dow, Mark; Aimon, Anthony; Warriner, Stuart; Nelson, Adam
• Is Part Of: Angewandte Chemie international edition. Volume 54:Issue 46(2015)
• Page Start: 13538
• Page End: 13544
• Publication Date: 2015-09-11
• Subjects: activity‐directed synthesis -- agonists -- bioactive molecules -- carbenoids -- reaction discovery; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201506944
• Languages: English
• ISSNs: 1433-7851

Abstract

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. 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 the highly efficient exploration of chemical space.