Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 17, Issue 24, Pages 6836-6840Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2007.10.024
Keywords
necroptosis; cell death; caspase-independent; necrosis; [1,2,3]Thiadiazole
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Funding
- NINDS NIH HHS [R21 NS067497, U01 NS050560, U01 NS050560-01A2] Funding Source: Medline
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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.
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