期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 19, 页码 11195-11214出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01128
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资金
- National Natural Science Foundation of China [81573313]
- Six Talent Peaks Project of Jiangsu Province [SWYY-107]
- Jiangsu Province 333 Project
- Qinglan Project of Jiangsu Province of China
- 111 Center from Ministry of Education of China
- State Administration of Foreign Experts Affairs of China [B18056]
- Innovative Research Team in University [IRT_15R63]
- Establishment and application of key technology system for obtaining and identifying effective/active small molecules of natural medicine [2017ZX09101003-001-007]
The thioredoxin system plays an important role in cancer cells. Inhibiting thioredoxin reductase (TrxR) has emerged as an effective strategy to selectively target cancer cells. Withangulatin A (WA), a natural product extracted from the whole herb of Physalis angulata L. (Solanaceae), exhibits potent anticancer activity and other diverse pharmacological activities. To improve activity and targeting, we designed and prepared 41 semisynthetic analogues of WA. Biological evaluation indicated that the most promising compound 13a displayed the most significant effect on HT-29 cells (human colon cancer cells) (IC50 = 0.08 mu M). A structure-activity relationship study indicated that alpha,beta-unsaturated ketones and ester are necessary groups, allowing 13a to undergo Michael addition reactions with mercaptan and selenol. Liquid chromatography-mass spectrometry (LC-MS) analysis confirmed that 13a modified selenocysteine 498 (U) residues in the redox centers of TrxR, resulting in enzyme inhibition. Therefore, compound 13a acts as a novel TrxR inhibitor and may be a promising candidate for cancer intervention.
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