Ruthenium half-sandwich complexes as protein kinase inhibitors

Since 2004, the Meggers group has established strategies for the design of protein kinase inhibitors by morphing indolocarbazole alkaloids (i.e. staurosporine) into chemically inert metallo-organic compounds. Ruthenium half-sandwich constructions bearing pyridocarbazole, cyclopentadienyl and carbon monoxide building blocks have been identified as highly potent and extremely selective inhibitors for Pim-1 and GSK-3. Synthetic modification of this scaffold for the development of improved inhibitors for these and other kinases is the topic of this thesis.*;In Chapter 2, a third generation strategy for the synthesis of the pyridocarbazole ligand is presented. From this, the synthesis of over a dozen modified complexes is described. The influence of new pyridocarbazole substituents on potency and selectivity for GSK-3 and Pim-1 is also investigated. From this, ruthenium pyridocarbazole 2.48 was discovered as the first organometallic picomolar inhibitor for GSK-3 (0.3 nM, 100 muM ATP), also displaying an excellent cellular potency against certain cancer cell lines.*;In Chapter 3, work towards the synthesis of a potential femtomolar inhibitor for GSK-3 is disclosed. With an IC50 value of at least 40 pM, ( RRu)-3.1 is one of the highest affinity ligands for a protein kinase known to date. Furthermore, a co-crystal structure of (RRu)-3.1 bound in the ATP-site of GSK-3beta was successfully solved and refined to 2.4 A.*;In Chapter 4, utilization of a library of organometallic scaffolds assists in the discovery of two novel kinase targets. Ruthenium pyridocarbazole ( RRu)-4.5 was determined to be a 45 nM inhibitor for MST-1 (100 microM ATP) and displays a promising selectivity profile when compared to other closely related Ste-20 kinases. In addition, ruthenium pyridocarbazole (SRu)-4.13a was determined to be a 30 nM inhibitor for TrkA (100 muM ATP) displaying an outstanding selectivity profile in a panel of 50 kinases.*;In Chapter 5, synthetic access to the class of lactam ruthenium pyridocarbazoles is presented. Previous binding preferences of the half-sandwich scaffold have switched from GSK-3/Pim-1 selectivity to MLCK/TrkA and CLK-2/PKG-1beta selectivity. In addition, with an IC50 value of 6 nM against TrkA (100 muM ATP) and remarkable selectivity over GSK-3, MLCK, and Pim-1, lactam ruthenium pyridocarbazole (RRu)-5.28 has the potential to be the most selective inhibitor for TrkA yet reported.*;*Please refer to dissertation for diagrams.