Robertson Mark J, Horatscheck André, Sauer Samantha, von Kleist Lisa, Baker Jennifer R, Stahlschmidt Wiebke, Nazaré Marc, Whiting Ainslie, Chau Ngoc, Robinson Phillip J, Haucke Volker, McCluskey Adam
Chemistry, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
Leibniz Institut für Molekulare Pharmakologie & Freie Universität Berlin, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Org Biomol Chem. 2016 Nov 29;14(47):11266-11278. doi: 10.1039/c6ob02308h.
The development of a (Z)-5-((6,8-dichloro-4-oxo-4H-chromen-3-yl)methylene)-2-thioxothiazolidin-4-one (2), rhodanine-based lead that led to the Pitstop® 2 family of clathrin inhibitors is described herein. Head group substitution and bioisosteric replacement of the rhodanine core with a 2-aminothiazol-4(5H)-one scaffold eliminated off target dynamin activity. A series of N-substituents gave first phenylglycine (20, IC ∼ 20 μM) then phenyl (25, IC ∼ 7.1 μM) and 1-napthyl sulfonamide (26, Pitstop® 2 compound, IC ∼ 1.9 μM) analogues with good activity, validating this approach. A final library exploring the head group resulted in three analogues displaying either slight improvements or comparable activity (33, 38, and 29 with IC ∼ 1.4, 1.6 and 1.8 μM respectively) and nine others with IC < 10 μM. These results were rationalized using in silico docking studies. Docking studies predicted enhanced Pitstop® 2 family binding, not a loss of binding, within the Pistop® groove of the reported clathrin mutant invalidating recent assumptions of poor selectivity for this family of clathrin inhibitors.
本文描述了一种(Z)-5-((6,8-二氯-4-氧代-4H-色烯-3-基)亚甲基)-2-硫代噻唑烷-4-酮(2)的开发，这是一种基于若丹宁的先导化合物，它导致了Pitstop® 2家族的网格蛋白抑制剂的产生。用2-氨基噻唑-4(5H)-酮支架对若丹宁核心进行头基取代和生物电子等排体取代消除了脱靶的发动蛋白活性。一系列N-取代基首先得到苯甘氨酸(20，IC ∼ 20 μM)，然后是苯基(25，IC ∼ 7.1 μM)和1-萘基磺酰胺(26，Pitstop® 2化合物，IC ∼ 1.9 μM)类似物，它们具有良好的活性，验证了这种方法。最后一个探索头基的文库产生了三种活性略有提高或相当的类似物(33、38和29，IC分别约为1.4、1.6和1.8 μM)以及另外九种IC < 10 μM的类似物。使用计算机对接研究对这些结果进行了合理化分析。对接研究预测，在报道的网格蛋白突变体的Pistop®凹槽内，Pitstop® 2家族的结合增强，而不是丧失结合，这推翻了最近关于该家族网格蛋白抑制剂选择性差的假设。
