The synthesis and evaluation of organoruthenium protein kinase inhibitors

The current use of metal complexes in medicine is primarily based on an interaction of the metal center itself with a ligand in the biological environment. It was envisioned that metal complexes can alternatively be used as stable three dimensional entities as tools for disrupting biological interactions. An introduction into the potential utility of this concept is presented in Chapter 1 including initial inhibitor design strategy and prospective contributions to the field of kinase inhibition. ^ The starting point for inhibitor design was based on the ATP-competitive indolocarbazole class of natural products, with staurosporine being its most prominent but unselective member. It was envisioned that by replacing the carbohydrate moiety of staurosporine with a metal center and ligand sphere, and the aglycon with a bidentate coordinating entity that inhibitors with new and interesting properties could be prepared.* ^ The first important step in accomplishing this goal is the establishment of a stable coordinating motif which contains a planar hydrophobic entity and lactam or imide functionality capable of undergo key hydrogen bonding interactions with the kinase active site. Chapter 2 describes the evolution of this process recapping the work of multiple Meggers group members including myself in the eventual development of a stable bidentate chelate which contains a pyridocarbazole base with a favorable bite angle leading to the preparation of stable ruthenium complexes.* ^ Having the pyridocarbazole based stable chelate in hand; a detailed evaluation of coordination chemistry and kinase inhibition was undertaken. Chapter 3 describes the evaluation of initial complexes leading to the discovery of a potent and selective inhibitor for GSK3 and Pim1 kinases.* ^ Cocrystallization of our complexes in the active site in Pim1 revealed important interactions and that the metal center itself is not involved in any interaction with the enzyme, but acts simply as a central cog projecting its ligands into the three dimensional space. Chapter 3 also describes subsequent alternative pyridocarbazole syntheses eventually providing ready access to modified pyridocarbazole ligands. ^ To investigate the effect of the ligand sphere in addition to the pyridocarbazole, a precursor complex containing four leaving group ligands was synthesized and utilized as is discussed in detail in Chapter 4. Combinatorial ligand substitution libraries were prepared and screened against the kinases of choice leading to the discovery of inhibitors for GSK3, Pim1, and MSK1 in addition to enlightening structure activity relationship studies.* ^ In the interest of modifying the otherwise unsubstituted cyclopentadienyl ring of the initial inhibitor in an efficient manner, an activated ester derivative was prepared. By using a diverse library of modified amines, amide containing inhibitors with increased potency for Pim1 and GSK3 relative to the initial scaffold were obtained.*^ Overall the research conducted has proven that metal containing scaffolds can be stable kinase inhibitors and exhibit properties of potency and selectivity which are competitive with the best known fully organic kinase inhibitors. ^ *Please refer to dissertation for diagrams.