Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Bioorg Med Chem. 2012 Feb 1;20(3):1319-36. doi: 10.1016/j.bmc.2011.12.011. Epub 2011 Dec 22.
An aryl-substituted isobenzofuran-1(3H)-one lead compound was identified from a high throughput screen designed to find inhibitors of the lymphocyte pore-forming protein perforin. A series of analogs were then designed and prepared, exploring structure-activity relationships through variation of 2-thioxoimidazolidin-4-one and furan subunits on an isobenzofuranone core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 natural killer effector cells was determined. Several compounds showed excellent activity at concentrations that were non-toxic to the killer cells. This series represents a significant improvement on previous classes of compounds, being substantially more potent and largely retaining activity in the presence of serum.
从一个旨在寻找淋巴细胞穿孔蛋白穿孔素抑制剂的高通量筛选中鉴定出一种芳基取代的异苯并呋喃-1(3H)-酮先导化合物。然后设计并制备了一系列类似物，通过异苯并呋喃酮核心上 2-硫代噁唑烷-4-酮和呋喃亚基的变化来探索构效关系。测定了所得化合物抑制分离的穿孔素蛋白和完整 KHYG-1 自然杀伤效应细胞原位递送的穿孔素的裂解活性的能力。几种化合物在对杀伤细胞无毒的浓度下表现出优异的活性。该系列代表了对以前化合物类别的重大改进，其效力大大提高，并且在存在血清的情况下基本保持活性。
