From ruthenium to platinum: The development of organometallic complexes for use as enzyme inhibitors

The vast majority of metals currently used in medicine take advantage of the reactivity of the metal center to derive their desired medicinal properties. The Meggers group envisioned an alternative strategy for using metals: as structural scaffolds in which there is no reaction at the metal center. In such complexes the metal atom is only used to build stable three-dimensional structures in which the entire structure is involved in elucidating a biological response as opposed to a reaction at the metal center. This design strategy is introduced in Chapter 1 as are the initial target protein kinases. This design strategy required the adaptation of a known kinase inhibitor (staurosporine) into a bidentate chelating ligand followed by the choice of an appropriate metal (ruthenium) to form stable complexes. Following this strategy led to the development of compound 2.16 by Howard Bregman as a low nanomolar inhibitor of glycogen synthase kinase 3 (GSK3) and the kinase Pim1. This initial success is described in Chapter 2. Chapter 3 describes my efforts to improve compound 2.16. The initial success of compound 2.16 led us to undertake a more thorough study of its binding properties via molecular modeling. These studies ultimately led to the identification of compound 3.3 as a potential improvement over 2.16 in terms of binding affinity. Compound 3.3 was prepared and tested for activity. As predicted by the modeling, 3.3 is a factor of 10X more potent than 2.14 and has improved solubility and in vivo biological activity.* With the success of 3.3 a more traditional structure-activity-relationship study was undertaken in which a number of modifications to the overall scaffold were made and evaluated for potency, leading to further gains in both potency and selectivity. Chapter 4 describes efforts to explore metals other than ruthenium. Initially the osmium homolog of 3.3 was prepared and studied. Cocrystallization with Pim1 reveals that this homolog binds in an identical fashion to 3.3 confirming the hypothesis that the metal only serves as a structural scaffold. While osmium provides structures with similar geometries to ruthenium, preparing platinum complexes affords the opportunity to prepare structures with different geometries. Through the development of a precursor with two leaving groups, two sequential libraries were prepared and screened against target kinases, with the best hit from the first library being the lead structure/starting material for the second library. This strategy yielded compound 4.28 as a low nanomolar inhibitor for the kinase GSK3.* Thus far, the developed inhibitors largely target GSK3 and Pim1. Chapter 5 describes efforts to prepare inhibitors for other targets. Using a combination of structure-based drug design and combinatorial chemistry, a low nanomolar inhibitor for the lipid kinase PI3K was developed. In addition, the identified modifications resulted in an impressive switch in selectivity as compound 5.19 has only micromolar affinity for GSK3 and Pim1.* Branching out from kinases was explored by attempting to prepare inhibitors of the interaction of murine double minute protein (MDM2) with p53 (disruption of this interaction is an important target in cancer therapy). Utilizing modeling, several organometallic scaffolds were identified which closely mimic a known benzodiaepinedione MDM2 inhibitor. The identified targets were then prepared and tested against MDM2 resulting in the identification of compound 5.29 as a lead structure with an IC50 of 80 μM.* Overall, the research presented has shown that it is possible to use a metal center purely as a structural scaffold. The metal center is used to present various functional groups to the active site by arranging various ligands around the metal. The developed complexes have been shown to be highly potent, selective, and stable enzyme inhibitors. *Please refer to dissertation for diagrams