Activity‐Directed Synthesis with Intermolecular Reactions: Development of a Fragment into a Range of Androgen Receptor Agonists

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.

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

“…[75] Thev ersatility of rhodium carbenes,w hich were formed from diazo compounds,tobuild different ring systems by different cyclization reactions was exploited to enrich the collection, which was then assayed to identify androgen receptor agonists.F or the reactions,a96 well plate was used, and twelve differently substituted a-diazo arylamide substrates were employed in combination with different rhodium catalysts and solvents, leading to 96 different reaction conditions.A fter 48 hours, metal contaminants and the solvents were removed, and the reaction mixtures were tested in an assay to identify the androgen receptor agonist properties of the products by FRET (Fçrster resonance transfer) techniques.T he four substrates that yielded highly active product mixtures were then used for the next round of reaction/screening (round 2) together with two that had not shown reactivity as negative controls.S olvent and catalyst were varied, and in this screening round, the concentration of the compounds was reduced by afactor of ten to identify more potent molecules. Thet hird reaction setup included the two most active substrates from the previous round as well as four structurally similar substrates along with various solvents and catalysts.In this round, the concentration was again reduced by afactor of ten.…”

Synthesis of Carbon‐Branched Sugars Involving an Unprecedented 1,5‐ or 1,6‐Alkyl Transposition Reaction

“…Application of the similar method on 3‐deoxygalactal derivative 15 , synthesized from 14 , provided the corresponding 1,6‐anhydro 2‐( p ‐methoxybenzyl) 3‐deoxy galactose derivative 16 as a single diastereomer in moderate yield (Table , entry 2). Interestingly, 6‐ O ‐( p ‐methoxybenzyl)‐3,4‐dideoxy glucal 18 , obtained by the p ‐methoxybenzylation of 17 , upon treating with TMSOTf provided a 1:1 diastereomeric mixture of 2‐ C ‐branched levoglucosan derivatives 19a and 19b via an unprecedented 1,6‐migration of the p ‐methoxybenzyl (PMB) group.…”

Streamlining bioactive molecular discovery through integration and automation

“…The activity-directed synthesis of androgen receptor agonists exploited metal-catalysed reactions that had many possible outcomes ( Figure 5). 49,50 Here, biological evaluation of the crude reaction products enabled both the ligand structure and the corresponding synthetic route to be optimised in parallel.…”

“…47 Activity-directed synthesis (ADS) is a function-directed approach that borrows some concepts from the emergence of biosynthetic pathways that yield natural products. 48,49 A conceptually-similar approachsynthetic fermentationhas also been developed, and has been exemplified in the discovery of -peptide-based inhibitors of hepatitis C virus (HCV) NS3/4A protease. 50 ADS and synthetic fermentation are complementary to dynamic combinatorial chemistry in which the most potent ligands are favoured via synthesis under thermodynamic control in the presence of a target protein.…”