. The proposed research plan describes the development of synthetic systems that emulate the properties found within the active sites of monooxyenases in order to probe metal-mediated activation of dioxygen. Two key design features utilized are incorporation of intramolecular hydrogen bonding (H-bond) networks within the secondary coordination sphere and the use of redox-active ligands within the primary coordination sphere. Coupling these features into a single ligand system represents an advance in molecular design that should allow for the isolation of Fe?oxo species that mimic the structures of the intermediates produced by P450 during activation of O2. This approach utilizes tridentate redox-active ligands with H-bond acceptors positioned within the secondary coordination sphere. One advantage of the approach is that additional ligands can be readily coordinated to the metal center; thus, several different variants can be prepared, characterized, and screened for function. In particular, iron complexes with axial thiolate donors are proposed that would simulate many of the structural features found within the active sites of the cyctochrome P450 monooxygenases. Similar to these enzymes, the metal ions in the proposed complexes are expected to bind and activate dioxygen (O2) to form H-bond stabilized peroxo (O22?) or oxo (O2?) units capable of functionalizing C?H bonds of substrates. Therefore, reactivity studies with O2 and hydrocarbon substrates are also proposed in which the generated products will be characterized using spectroscopic and computational techniques that include UV-vis, EPR, Mssbauer, and FTIR spectroscopies and density functional theory. These studies are expected to lead to a greater understanding of the biochemistries of monooxygenase active sites and how earth abundant metals are capable of efficiently activating C?H bonds of inert substrates.
. Monooxygenases are a ubiquitous class of enzymes that perform a wide variety of fundamental biological transformations from steroid biosynthesis to phase I drug metabolism, amongst others. This project describes an advance in the molecular design of complexes that mimic the reactivity of monooxygenases through the use of a framework that combines, within a single ligand, the ability to both shuttle electrons to and from substrates and provide a stabilizing hydrogen bonding network to the distal coordination environment of the metal center, which are the two aspects of monooxygenase active sites that are believed to be important to function. A family of additional ligands for these monooxygenase mimics will be screened to provide further insight into the structural aspects that lead to function within the active sites of these biologically relevant enzymes.
| Cook, Sarah A; Bogart, Justin A; Levi, Noam et al. (2018) Mononuclear complexes of a tridentate redox-active ligand with sulfonamido groups: structure, properties, and reactivity. Chem Sci 9:6540-6547 |
