Krishnathas Robin, Bonke Erik, Dröse Stefan, Zickermann Volker, Nasiri Hamid R
Johann Wolfgang Goethe-University Frankfurt , Max-von-Laue-Straße 7 , D-60438 Frankfurt am Main , Germany . Email:
Department of Anaesthesiology , Intensive-Care Medicine and Pain Therapy , University Hospital Frankfurt , 60590 Frankfurt am Main , Germany.
Medchemcomm. 2017 Feb 20;8(3):657-661. doi: 10.1039/c6md00655h. eCollection 2017 Mar 1.
By probing the quinone substrate binding site of mitochondrial complex I with a focused set of quinazoline-based compounds, we identified substitution patterns as being critical for the observed inhibition. The structure activity relationship study also resulted in the discovery of the quinazoline 4--[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine () as a highly potent inhibitor of the multisubunit membrane protein. specifically and effectively reduces the mitochondrial complex I-dependent respiration with no effect on the respiratory chain complexes II-IV. Similar to established Q-site inhibitors, elicits the release of reactive oxygen species at the flavin site of mitochondrial complex I. Recently, was nominated as a lead compound for the treatment of Huntingtons disease. Our results challenge the postulated primary mode-of-action of as an inhibitor of NF-κB pathway activation and/or store-operated calcium influx.
通过用一组特定的喹唑啉类化合物探测线粒体复合物I的醌底物结合位点，我们确定了取代模式对所观察到的抑制作用至关重要。构效关系研究还发现喹唑啉4-[2-(4-苯氧基苯基)乙基]喹唑啉-4,6-二胺（）是一种多亚基膜蛋白的高效抑制剂。它能特异性且有效地降低线粒体复合物I依赖的呼吸作用，而对呼吸链复合物II-IV没有影响。与已有的Q位点抑制剂类似，它能在线粒体复合物I的黄素位点引发活性氧的释放。最近，它被提名为治疗亨廷顿舞蹈病的先导化合物。我们的结果对其作为NF-κB途径激活和/或储存操纵性钙内流抑制剂的假定主要作用模式提出了挑战。
