Discovery of novel NO-releasing celastrol derivatives with Hsp90 inhibition and cytotoxic activities

被引：11

作者：

Li, Na ^{[1
]}

Xu, Manyi ^{[1
]}

Bao, Na ^{[1
]}

Shi, Wei ^{[1
]}

Li, Qixing ^{[1
]}

Zhang, Xiaowei ^{[1
]}

Sun, Jianbo ^{[1
]}

Chen, Li ^{[1
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Dept Nat Med Chem, Sch Tradit Chinese Pharm, 24 Tong Jia Xiang, Nanjing 210009, Jiangsu, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 160卷

关键词：

Celastrol; Nitric oxide; Hsp; 90; Apoptosis; Cytotoxicity; NITRIC-OXIDE; BIOLOGICAL EVALUATION; ANTICANCER ACTIVITY; IN-VITRO; DESIGN; CANCER; ACID; HSP90-CDC37; COCHAPERONE; MECHANISM;

D O I：

10.1016/j.ejmech.2018.10.013

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To develop multifunctional drugs, a series of celastrol/NO donor hybrids were designed, synthesized and evaluated. The detection of NO release amounts showed that the more NO of these hybrids released, the more tumor cells were inhibited. lib, which released the highest level of NO in vitro, exhibited superior potency (lC(50) = 0.48 +/- 0.06 mu M) compared to the other compounds. Further pharmacological studies showed that lib induced dysregulations of the Hsp90 clients (Akt and Cdk4), apoptosis, and cell cycle arrested at G(0)/G(1) phase against A549 cells. These results suggested that inhibition of Hsp90 and release of NO was synergistic in cancer cells. Overall, the NO-releasing capacity and the inhibition of Hsp90 pathway signaling might explain the potent anti-proliferative activities of these compounds. (C) 2018 Elsevier Masson SAS. All rights reserved.

引用

页码：1 / 8

页数：8

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