Targeting Adenine-Nucleotide-Dependent Enzymes with Metal-Containing Compounds

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Metal complexes play an increasingly important role as structurally sophisticated globular scaffolds for the design of enzyme inhibitors. Previous work from this laboratory was focused entirely on the inhibition of protein kinases with a single molecular scaffold derived from the natural product staurosporine. This proposal has therefore the main objective to generalize previous work by (1.) designing novel metal-based molecular scaffolds and (2.) applying them to the development of inhibitors of the large and biologically important family of adenine-nucleotide-dependent proteins and enzymes. In a first phase, novel pharmacophore chelate ligands will be designed and synthesized, in particular 3-(2-pyridyl)-1,8-naphthalimide, 3-(2-pyridyl)-1,6-phthalimide, benzo[h]quinoline-6,7-dicarboximide, 6-amino-1,5-phenanthroline, 7-amino-1,8-phenanthroline, 4-aminobenzo[h]quinazoline, and 8-(2-pyridyl)adenine. In a second phase, their coordination and organometallic chemistry will be investigated and finally, in a third phase the biological activities of derived metal complexes will be explored and analyzed. It is expected that this project will lead to an improved understanding of the molecular recognition of proteins by metal complexes and to the development of novel probes and drug candidates.