jm0c01128_si_001.pdf (16.09 MB)
Download fileDesign and SAR of Withangulatin A Analogues that Act as Covalent TrxR Inhibitors through the Michael Addition Reaction Showing Potential in Cancer Treatment
journal contribution
posted on 2020-09-17, 14:34 authored by Cheng Wang, Shang Li, Jinhua Zhao, Huali Yang, Fucheng Yin, Ming Ding, Jianguang Luo, Xiaobing Wang, Lingyi KongThe 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 μM).
A structure–activity relationship study indicated that α,β-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.