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

金属络合物作为结构复杂的球形支架在酶抑制剂的设计中发挥着越来越重要的作用。该实验室以前的工作完全集中在用天然产物星形孢子素衍生的单一分子支架抑制蛋白激酶。因此，本提案的主要目标是通过(1)概括以前的工作。设计新型金属基分子支架和(2)将它们应用于腺嘌呤核苷酸依赖蛋白和酶这一具有重要生物学意义的大家族的抑制剂的开发。在第一阶段，将设计和合成新型的药效团螯合配体，特别是3-(2-吡啶)-1，8-萘酰亚胺、3-(2-吡啶)-1，6-邻苯二甲酰亚胺、苯并[h]喹啉-6，7-二羧亚胺、6-氨基-1，5-菲咯啉、7-氨基-1，8-菲咯啉、4-氨基苯并[h]喹唑啉和8-(2-吡啶)腺嘌呤。在第二阶段，将研究它们的配位和有机金属化学，最后，在第三阶段，将探索和分析衍生金属配合物的生物活性。预计该项目将有助于更好地理解金属络合物对蛋白质的分子识别作用，并开发新的探针和候选药物。

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.