Current approaches for the discovery of bioactive molecules tend to treat all molecules in large collections with the same significance regardless of their ultimate biological activity. Furthermore, these approaches exploit a limited palette of reliable well-working reactions, that have been optimised for the preparation of individual compounds.
This thesis describes the development of a new discovery approach –Activity-Directed Synthesis. The approach aims to merge the discovery of small bioactive molecules with the emergence of a synthetic route. In this regard Activity-Directed Synthesis may be analogous with the evolution of biosynthetic pathways as is observed in Nature. For the implementation of Activity-Directed Synthesis, a well-studied chemical toolbox – metal carbenoid chemistry – that has been underutilised in bioactive molecule discovery was used. The approach was demonstrated in the discovery of novel chemotypes of small bioactive molecules that agonise the Androgen Receptor. Both intra- and intermolecular reactions were exploited in sequential rounds of carbenoid reactions which had many alternative outcomes. Three iterative rounds of screening crude reaction mixtures and design of subsequent reaction arrays enabled the rapid discovery of reactions that yielded bioactive products. Hence small-molecule modulators of the Androgen Receptor, based on scaffolds with no previously annotated activity were discovered. A total of 272 microreactions was performed in the case of intramolecular reactions and a total of 326 microreactions was performed in the case of intermolecular reactions. In the case of the intramolecular chemistry, it was demonstrated retrospectively that the approach enabled the parallel optimisation of both the structure of bioactive molecules and the routes for their synthesis. In the case of the intermolecular chemistry, it was demonstrated that non-exhaustive reaction arrays could still lead to the discovery of sub-micromolar modulators of the Androgen Receptor, greatly improving the efficiency of Activity-Directed Synthesis
