Exploring Chemical Space with Organometallics: Ruthenium Complexes as Protein Kinase Inhibitors

Abstract

Complementing organic elements with a metal center provides new opportunities for building three-dimensional structures with unique and defined shapes. Such access to unexplored chemical space may lead to the discovery of molecules with unprecedented properties. Along these lines, this account article describes our successful design of highly potent and selective ruthenium-based inhibitors for the protein kinases GSK-3 and Pim-1 by using the class of indolocarbazole alkaloids as a lead structure. The described ruthenium complexes are kinetically inert scaffolds in which the ruthenium has the function to organize the orientation of the organic ligands in the three-dimensional space.

• 1 Introduction

• 1.1 Biologically Relevant Chemical Space

• 1.2 Organic vs. Organometallic Compounds

• 1.3 Ruthenium as a Virtual Octahedral Carbon

• 2 Mimicking the Natural Product Staurosporine with Simple Ruthenium Complexes

• 3 Synthesis of Cycloruthenated Pyrido[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-diones

• 4 Discovery of Ruthenium Complexes as Protein Kinase ­Inhibitors

• 4.1 Octahedral Complexes

• 4.2 Half-Sandwich Complexes

• 5 Structures of Ruthenium Half-Sandwich Complexes Bound to Protein Kinase Pim-1

• 6 GSK-3 Inhibition in Mammalian Cells, Frog Embryos, and Zebrafish Embryos

• 7 Summary and Outlook

Key words

bioorganometallic chemistry - protein kinases - inhibitors - ruthenium - mammalian cells

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3

We are here using a more general definition of the term ‘organometallic’ which includes all metal/organic hybrid compounds without restriction to substances with metal-carbon bonds.