2. Academic Validation
  3. Enantiomeric profiling of a chiral benzothiazole necroptosis inhibitor

Enantiomeric profiling of a chiral benzothiazole necroptosis inhibitor

  • Bioorg Med Chem Lett. 2021 Jul 1:43:128084. doi: 10.1016/j.bmcl.2021.128084.
Jing Zhu 1,  Zhuo Qu 2,  Jiaxuan Huang 2,  Lijuan Xu 1,  Hao Zhang 1,  Jianqiang Yu 2,  Wannian Zhang 3,  Chunlin Zhuang 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
  • 2 School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China.
  • 3 School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: zhangwnk@hotmail.com.
  • 4 School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: zclnathan@163.com.
PMID: 33964444 DOI: 10.1016/j.bmcl.2021.128084
Abstract

Necroptosis is a form of programmed cell death that contributes to the pathophysiology of multiple diseases. Development of small-molecule anti-necroptosis agents has great promising clinical therapeutic relevance. The benzothiazole compounds were discovered by our group from an in-house fluorine-containing compound library as potent Necroptosis inhibitors. Herein, a chiral dimethylcyclopropyl benzothiazole Necroptosis Inhibitor was developed and the enantiomeric profiling resulted that the (S) form was generally more potent than the (R) counterpart in 2 ~ 4-fold toward cell Necroptosis, receptor-interacting protein (RIP) kinases 1 and 3. The chiral compounds could significantly inhibit the expression of the phosphorylation of RIPK1, RIPK3 and MLKL in necroptotic cells. The molecular modelling studies predicted the binding modes of the enantiomers with RIP and explained their activity differences, guiding further rational design of the chiral Necroptosis inhibitors.

Keywords

Benzothiazole; Chirality; Enantiomeric profiling; Necroptosis; RIP kinase.

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