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

用含金属化合物靶向腺嘌呤核苷酸依赖性酶

基本信息

批准号：
216576147
负责人：
Professor Dr. Eric Leif Meggers
金额：
--
依托单位：
Fachgebiet Chemische Biologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/216576147?language=en
关键词：
Targeting Adenine Nucleotide Dependent Enzymes

项目摘要

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.

金属配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来自天然产物星形孢菌素的单一分子支架抑制蛋白激酶上。因此，本建议的主要目标是推广以前的工作（1）。设计新型金属基分子支架和（2.）将它们应用于开发生物学上重要的腺嘌呤核苷酸依赖性蛋白质和酶的大家族的抑制剂。在第一阶段，将设计和合成新的药效团螯合配体，特别是3-（2-吡啶基）-1，8-萘二甲酰亚胺、3-（2-吡啶基）-1，6-邻苯二甲酰亚胺、苯并[h]喹啉-6，7-二甲酰亚胺、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-吡啶基）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络合物的生物活性。预计该项目将导致对金属络合物对蛋白质的分子识别的更好理解，并开发新的探针和候选药物。