Development of new N-Arylbenzamides as STAT3 Dimerization Inhibitors.
Development of new N-Arylbenzamides as STAT3 Dimerization Inhibitors.
复制标题
DOI：
10.1039/c3md20323a
复制
发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Lawrence NJ
中科院分区：
文献类型：
--
作者：
Urlam MK;Pireddu R;Ge Y;Zhang X;Sun Y;Lawrence HR;Guida WC;Sebti SM;Lawrence NJ
邻甲苯磺酰基水杨酰胺S3 I-201（10）被用作设计和合成具有改善的药物样品质的新型STAT-3二聚化抑制剂的起始点。具有缺少O-甲苯磺酰基的较短酰胺接头的膦酸12 d和水杨酸13 f、13 g具有改善的STAT-3抑制活性。通过用5-氨基-2-羟基苯甲酸基团替换12 d的膦酸部分观察到的等效效力（如13 f中）进一步验证了5-氨基-2-羟基苯甲酸作为磷酸酪氨酸模拟物。水杨酸13 f显示出改善的全细胞活性。具有苯甲酰胺接头的水杨酸13的聚焦文库表明，疏水庚基和环己基是最佳耐受的R基团，并且联苯醚（作为Ar基团）显著有助于STAT 3抑制活性。我们的对接研究表明，12 d，13 f和13 g的酸性基团在p-Tyr-705结合位点以大致相似的方式相互作用，而苯氧基苯甲酰基和环己基苄基分别占据pY+1和pY-X疏水口袋。13 f的体外和基于细胞的效力保证了该支架作为STAT 3抑制剂的进一步开发。
The O-tosylsalicylamide S3I-201 (10) was used as a starting point for design and synthesis of novel STAT-3 dimerization inhibitors with improved drug-like qualities. The phosphonic acid 12d and salicylic acids 13f, 13g with a shorter amide linker lacking the O-tosyl group had improved STAT-3 inhibitory activity. The equivalent potencies observed by the replacement of phosphonic acid moiety of 12d with 5-amino-2-hydroxybenzoic acid group as in 13f further validates 5-amino-2-hydroxybenzoic acid as a phosphotyrosine mimic. The salicylic acid 13f displayed improved whole cell activity. The focused library of salicylic acids 13 with benzamide linker indicated that hydrophobic heptyl and cyclohexyl are the best tolerated R groups and a biphenyl ether (as the Ar group) significantly contributes to STAT3 inhibitory activity. Our docking studies indicated that the acidic groups of 12d, 13f and 13g interact in the p-Tyr-705 binding site in a broadly similar manner, while the phenoxybenzoyl group and the cyclohexylbenzyl group occupying pY+1 and pY-X hydrophobic pockets respectively. The in vitro and cell based potency of 13f warrants further development of this scaffold as STAT3 inhibitors.