Bioassay-guided fractionation of cells uncovers small molecules that bind receptors in new and unexpected
ways. These cellular metabolites emerge from evolution with complex molecular features preoptimized for
function. High stereochemical content, high globularity and diverse heteroatom content impart greater
specificity of protein binding and greater aqueous solubility than simple, flat and non-polar substances.
Parametrization of large molecular libraries have supported a correlation between evolutionary optimization
and therapeutic design: “drug” chemical space is optimized away from commercial building blocks and towards
natural products (NP space). These types of molecules represent a challenge to chemical synthesis, however,
and require the development of new chemical tools for optimization and human use.
This grant advances our work towards the rapid access and navigation of NP space. Our robust routes to
complex molecules have proven practical: synthesis allowed us to annotate and modify biological function.
Over the coming grant period we extend this approach into three areas. First, we develop the chemistry to
access two chemotypes with known phenotypic effects but unknown biological targets. One target has
stimulated the discovery of a new, stereoselective cross-coupling reaction, whereas another has inspired the
conversion of inert scaffolds to new warheads for protein adduction. Second, we describe rapid access to
complex ligands of known biological targets that embody ‘combinatorial’ aggregates of multiple proteins.
Diverse structural modifications of the complex small molecule will enable a search for selectivity among these
combinatorial targets with consequences for therapeutic development. Third, selectivity defines the future
goals of dual-catalytic cross-couplings to reach NP space: we seek to address substrate selectivity, relative
stereoselectivity and absolute stereoselectivity.