Structure-activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors
Structure-activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors
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DOI：
10.1016/j.bmcl.2007.10.024
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发表时间：
2007-12-15
影响因子：
2.7
通讯作者：
Cuny, Gregory D.
中科院分区：
文献类型：
--
作者：
Teng, Xin;Keys, Heather;Cuny, Gregory D.
坏死性凋亡是一种受调节的半胱天冬酶非依赖性细胞死亡机制，其导致类似于非调节性坏死的形态学特征。这种形式的细胞死亡可以在凋亡缺陷条件下用死亡受体家族配体在一系列细胞类型中诱导。一系列[1，2，3]噻二唑苯甲酰胺被发现是有效的坏死性凋亡抑制剂（称为坏死抑制素）。构效关系研究表明，在[1，2，3]噻二唑的4-位和5-位分别引入小环烷基（即环丙基）和2，6-二卤苄基酰胺是最佳的。此外，当苄基位置上存在小的烷基（即甲基）时，所有坏死性凋亡抑制活性均存在于（S）-对映异构体中。最后，用各种噻吩衍生物代替[1，2，3]噻二唑是可以容忍的，尽管观察到一些效力的侵蚀。(c)2007爱思唯尔有限公司保留所有权利。
Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling non-regulated necrosis. This form of cell death can be induced in an array of cell types in apoptotic deficient conditions with death receptor family ligands. A series of [1,2,3]thiadiazole benzylamides was found to be potent necroptosis inhibitors (called necrostatins). A structure-activity relationship study revealed that small cyclic alkyl groups (i.e. cyclopropyl) and 2,6-dihalobenzylamides at the 4- and 5-positions of the [1,2,3]thiadiazole, respectively, were optimal. In addition, when a small alkyl group (i.e. methyl) was present on the benzylic position all the necroptosis inhibitory activity resided with the (S)-enantiomer. Finally, replacement of the [1,2,3]thiadiazole with a variety of thiophene derivatives was tolerated, although some erosion of potency was observed. (c) 2007 Elsevier Ltd. All rights reserved.