Harnessing Late-Stage Functionalization for Medicinal Chemistry and Redshifting Azobenzenes for In Vivo Photopharmacology
Dr. David Konrad
Department Pharmazie, Ludwig-Maximilians-Universität München
Part 1: Late-stage functionalization (LSF) provides the opportunity to directly and economically modify small molecule scaffolds circumventing the need for alternate synthetic routes to install new substitution patterns. To date, however, only few applications of LSF in drug discovery have been published due to the difficulty in predicting the reaction outcome if multiple functional groups and various types of C–H bonds with different bond strength and stereoelectronic properties are present. To approach this challenge, we have built a semi-automated high throughput experimentation (HTE) platform. In a proof-of-concept study, we have investigated the regioselective introduction of boronic esters into advanced drug-like molecules, which serve as synthetic handles for installing a variety of different functional groups. Reactions with 39 substrates were tested with our HTE approach which culminated in the performance of 956 reactions. The generated reaction data along with a literature dataset was used to train graph neural networks that predict the reactivity of new substrates, such as the binary reaction outcome, yield and regioselectivity, with high accuracy.
Part 2: Photopharmaceuticals contain azobenzene fragments as ON- and OFF-switches, which allow for the control of biological functions with the spatiotemporal precision of light. Their use for in vivo photopharmacology and to move drug candidates into the clinic relies on the use of tissue-penetrating, non-hazardous red light. To this end, we have developed new substitution patterns with minimal changes to the structure and size of standard azobenzene to preserve the biological function of a photoswitchable ligand. Our data was used to establish a computational platform for the development of highly red-shifted azobenzenes and to synthesize a library of visible light-operated photopharmaceuticals.