Combinatorial Coordination Chemistry for Discovery of Therapeutic Metallocomplexes

Traditionally, drug discovery research has focused on the development of organic molecules as pharmacophores. Yet, their limited structural diversity makes it difficult for them to access other scaffolds that span the entirety of the biologically-relevant chemical space. Organotransition metal scaffolds are uniquely suited for the development of potential drug candidates as they can accommodate higher coordination numbers and access molecular geometries not possible with a purely organic framework. To exploit these advantages, we designed a water-promoted multi-component reaction for the combinatorial assembly of organoruthenium-arene complexes (C3A) for rapid assembly of Ru(II)-Arene Schiff-base (RAS) complexes for therapy.
We apply this combinatorial coordination chemistry methodology towards identification of highly active metallocomplexes for therapy. Most clinically-approved anticancer drugs induce DNA damage and activation of transcription factor p53, leading to a downstream induction of apoptosis. Some cancers may be inherently resistant or may acquire resistance by modulating their expression of apoptotic factors in favour of cell survival. I will discuss a phenotypic screening strategy that identified p53-independent RAS compounds with high potency in apoptosis-resistant colorectal cancer cells.
We have also extended this strategy towards developing RAS complexes that act against pathogenic bacteria by using endogenous formate metabolites. These complexes mediate activation of exogenous substrates including azide-caged and nitro-caged sulfanilamide antibiotics in the presence of native formate as well as direct reduction of dioxygen into ROS. In both cases, they exerted targeted antibacterial effects against formate-abundant methicillin-resistant S. aureus.