Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States.
Department of Chemistry & Biochemistry, University of Missouri St. Louis, St. Louis, MO 63121, United States.
Bioorg Med Chem. 2010 Mar 15;18(6):2265-2274. doi: 10.1016/j.bmc.2010.01.063. Epub 2010 Feb 4.
Two new monocyclic analogs of the natural AChE inhibitor cyclophostin and two exocyclic enol phosphates were synthesized. The potencies and mechanisms of inhibition of the bicyclic and monocyclic enol phosphonates and the exocyclic enol phosphates toward human AChE are examined. One diastereoisomer of the bicyclic phosphonate exhibits an IC(50) of 3 microM. Potency is only preserved when the cyclic enol phosphonate is intact and conjugated to an ester. Kinetic analysis indicates both a binding and a slow inactivation step for all active compounds. Mass spectrometric analysis indicates that the active site Ser is indeed phosphorylated by the bicyclic phosphonate.
合成了两种新型的天然 AChE 抑制剂环磷酰胺的单环类似物和两种外环烯醇磷酸酯。研究了双环和单环烯醇膦酸酯以及外环烯醇磷酸酯对人乙酰胆碱酯酶的抑制活性和作用机制。双环膦酸酯的一个非对映异构体对人乙酰胆碱酯酶的抑制活性（IC50）为 3μM。只有当环烯醇磷酸酯保持完整并与酯键共轭时，其活性才得以保留。动力学分析表明，所有活性化合物都存在结合和缓慢失活两个步骤。质谱分析表明，活性部位丝氨酸确实被双环磷酸酯所磷酸化。
