Teng Xin, Keys Heather, Jeevanandam Arumugasamy, Porco John A, Degterev Alexei, Yuan Junying, Cuny Gregory D
Laboratory for Drug Discovery in Neurodegeneration, Harvard Center for Neurodegeneration and Repair, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
Bioorg Med Chem Lett. 2007 Dec 15;17(24):6836-40. doi: 10.1016/j.bmcl.2007.10.024. Epub 2007 Oct 17.
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.
坏死性凋亡是一种受调控的非半胱天冬酶依赖性细胞死亡机制，其导致的形态学特征类似于非调控性坏死。在凋亡缺陷条件下，死亡受体家族配体可在一系列细胞类型中诱导这种细胞死亡形式。人们发现一系列[1,2,3]噻二唑苄胺是有效的坏死性凋亡抑制剂（称为坏死性凋亡抑制剂）。构效关系研究表明，[1,2,3]噻二唑的4位和5位分别具有小的环状烷基（即环丙基）和2,6-二卤代苄胺是最佳的。此外，当苄基位置存在小烷基（即甲基）时，所有坏死性凋亡抑制活性都存在于（S）-对映体中。最后，用各种噻吩衍生物取代[1,2,3]噻二唑是可以接受的，尽管观察到活性有所下降。
