Pyridocarbazole-Rhodium(III) Complexes as Protein Kinase Inhibitors

Inert metal complexes are sophisticated structural scaffolds for the design of enzyme inhibitors. Whereas previous work from our laboratory was predominantly based on ruthenium(II), this study evaluates the suitability of rhodium in the +3 oxidation state to serve as a structural centre for the design of inert metal-based enzyme inhibitors. Based on our established staurosporine-inspired metallo-pyridocarbazole scaffold, strategies for the convenient synthesis of rhodium(III)-pyridocarbazole complexes were developed and applied to the synthesis of protein kinase inhibitors. The structures of several rhodium complexes were investigated by Xray crystallography. A stability study confirmed the high kinetic inertness of such rhodium complexes under biologically relevant conditions, such as the presence of millimolar concentrations of thiols. Finally, an extremely potent, picomolar rhodium inhibitor for the protein kinase Pim1 was discovered. Thus, it can be concluded that rhodium(III) expands the toolbox for the design of inert metal complexes with biological activity.