Guo Kai, Mutter Roger, Heal William, Reddy Tummala R K, Cope Hannah, Pratt Steven, Thompson Mark J, Chen Beining
Department of Chemistry, University of Sheffield, Dainton Building, Brook Hill, Sheffield S3 7HF, UK.
Eur J Med Chem. 2008 Jan;43(1):93-106. doi: 10.1016/j.ejmech.2007.02.018. Epub 2007 Mar 12.
We report the preparation and screening of a set of 55 pyridine dicarbonitriles as potential prion disease therapeutics. Use of microwave irradiation in an attempt to improve the synthesis typically led to only small enhancement in yields but gave cleaner reactions facilitating product isolation. The library was analysed for binding to human prion protein (huPrPC) by surface plasmon resonance and for inhibition of the formation of its partially protease resistant isoform PrPSc in mouse brain cells (SMB). A total of 26 compounds were found to bind to huPrPC whilst 12 showed discernable inhibition of PrPSc formation, five displaying EC(50)s in the range 2.5-9microwo compounds were found to reduce PrPSc levels to below 30% relative to an untreated control at 50nM.
我们报告了一组55种吡啶二腈作为潜在朊病毒疾病治疗药物的制备和筛选情况。尝试使用微波辐射来改进合成方法，通常只会使产率略有提高，但反应更纯净，便于产物分离。通过表面等离子体共振分析该文库与人类朊病毒蛋白（huPrPC）的结合情况，并分析其对小鼠脑细胞（SMB）中部分蛋白酶抗性异构体PrPSc形成的抑制作用。总共发现26种化合物与huPrPC结合，同时有12种显示出对PrPSc形成有明显抑制作用，其中5种的半数有效浓度（EC50）在2.5 - 9微摩尔范围内，有2种化合物在50纳摩尔浓度下能将PrPSc水平相对于未处理对照降低至30%以下。
