Altmeyer Markus, Amtmann Eberhard, Heyl Carina, Marschner Aline, Scheidig Axel J, Klein Christian D
Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology, IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
Präklinische Targetentwicklung, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Bioorg Med Chem Lett. 2014 Nov 15;24(22):5310-4. doi: 10.1016/j.bmcl.2014.09.047. Epub 2014 Sep 23.
We identified and characterized β-aminoketones as prodrugs for irreversible MetAP inhibitors that are selective for the MetAP-1 subtype. β-Aminoketones with certain structural features form α,β-unsaturated ketones under physiological conditions, which bind covalently and selectively to cysteines in the S1 pocket of MetAP-1. The binding mode was confirmed by X-ray crystallography and assays with the MetAPs from Escherichia coli, Staphylococcus aureus and both human isoforms. The initially identified tetralone derivatives showed complete selectivity for E. coli MetAP versus human MetAP-1 and MetAP-2. Rational design of indanone analogs yielded compounds with selectivity for the human type-1 versus the human type-2 MetAP.
我们鉴定并表征了β-氨基酮作为不可逆的甲硫氨酸氨肽酶（MetAP）抑制剂的前药，这些抑制剂对MetAP-1亚型具有选择性。具有特定结构特征的β-氨基酮在生理条件下形成α,β-不饱和酮，其与MetAP-1的S1口袋中的半胱氨酸共价且选择性地结合。通过X射线晶体学以及对来自大肠杆菌、金黄色葡萄球菌和两种人类同工型的MetAP进行的测定，证实了这种结合模式。最初鉴定的四氢萘酮衍生物对大肠杆菌MetAP相对于人类MetAP-1和MetAP-2表现出完全的选择性。茚满酮类似物的合理设计产生了对人类1型MetAP相对于人类2型MetAP具有选择性的化合物。
