Abstract |
The alteration of redox homeostasis is a hallmark of cancer cells. As a critical player in regulating cellular redox signaling, thioredoxin reductase (TrxR) enzymes are increasingly recognized as attractive targets for anticancer drug development. We reported herein the natural product sanguinarine (SAN) as a potent inhibitor of TrxR with a new chemical scaffold. Inhibition of TrxR leads to accumulation of the oxidized thioredoxin, elicits oxidative stress, and finally promotes apoptosis of cancer cells. Further synthesis of different model compounds of SAN demonstrated that the phenanthridinium unit is responsible for the TrxR inhibition. The core structure of SAN, e.g., the phenanthridinium moiety, is different from those of known TrxR inhibitors, and thus SAN is a new chemical entity of TrxR inhibitors and may serve a lead for further development. In addition, as the phenanthridinium scaffold is widely present in natural products, the disclosure of TrxR inhibition by such unit sheds light in understanding the pharmacological actions of these molecules.
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Authors | Juan Yao, Dongzhu Duan, Zi-Long Song, Junmin Zhang, Jianguo Fang |
Journal | Free radical biology & medicine
(Free Radic Biol Med)
Vol. 152
Pg. 659-667
(05 20 2020)
ISSN: 1873-4596 [Electronic] United States |
PMID | 31931095
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2020 Elsevier Inc. All rights reserved. |
Chemical References |
- Benzophenanthridines
- Isoquinolines
- Thioredoxins
- sanguinarine
- Thioredoxin-Disulfide Reductase
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Topics |
- Apoptosis
- Benzophenanthridines
- Isoquinolines
- Oxidative Stress
- Thioredoxin-Disulfide Reductase
(metabolism)
- Thioredoxins
(metabolism)
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