一种新型的基于硝基苯并恶二唑的GSTP1-1抑制剂，具有前所未闻的作用机制和高稳定性。
A new nitrobenzoxadiazole-based GSTP1-1 inhibitor with a previously unheard of mechanism of action and high stability.
作者信息
Fulci Chiara, Rotili Dante, De Luca Anastasia, Stella Lorenzo, Morozzo Della Rocca Blasco, Forgione Mariantonietta, Di Paolo Veronica, Mai Antonello, Falconi Mattia, Quintieri Luigi, Caccuri Anna M
机构信息
a Department of Experimental Medicine and Surgery , University of Tor Vergata , Rome , Italy.
b Department of Drug Chemistry and Technologies , University of Rome "Sapienza" , Rome , Italy.
出版信息
J Enzyme Inhib Med Chem. 2017 Dec;32(1):240-247. doi: 10.1080/14756366.2016.1247059.
CONTEXT
The nitrobezoxadiazole derivative NBDHEX is a potent inhibitor of glutathione transferase P1-1 (GSTP1-1) endowed with outstanding anticancer activity in different tumor models.
OBJECTIVE
To characterize by in vitro biochemical and in silico studies the NBDHEX analogues named MC2752 and MC2753.
MATERIALS AND METHODS
Synthesis of MC2752 and MC2753, biochemical assays and in silico docking and normal-mode analyses.
RESULTS
The presence of a hydrophobic moiety in the side chain of MC2753 confers unique features to this molecule. Unlike its parent drug NBDHEX, MC2753 does not require GSH to trigger the dissociation of the complex between GSTP1-1 and TRAF2, and displays high stability towards the nucleophilic attack of the tripeptide under physiological conditions.
DISCUSSION AND CONCLUSION
MC2753 may represent a lead compound for the development of novel GSTP1-1 inhibitors not affected in their anticancer action by fluctuations of cellular GSH levels, and characterized by an increased half-life in vivo.
背景
硝基苯并恶二唑衍生物NBDHEX是谷胱甘肽转移酶P1-1（GSTP1-1）的强效抑制剂，在不同肿瘤模型中具有出色的抗癌活性。
目的
通过体外生化和计算机模拟研究对名为MC2752和MC2753的NBDHEX类似物进行表征。
材料与方法
MC2752和MC2753的合成、生化测定以及计算机模拟对接和正常模式分析。
结果
MC2753侧链中疏水部分的存在赋予了该分子独特的特性。与母体药物NBDHEX不同，MC2753不需要谷胱甘肽来触发GSTP1-1与TRAF2之间复合物的解离，并且在生理条件下对三肽的亲核攻击表现出高稳定性。
讨论与结论
MC2753可能代表一种先导化合物，用于开发新型GSTP1-1抑制剂，其抗癌作用不受细胞谷胱甘肽水平波动的影响，并且在体内具有延长的半衰期。
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