Discovery of NO Donor-Aurovertin Hybrids as Dual Ferroptosis and Apoptosis Inducers for Treating Triple Negative Breast Cancer

Lie Feng Ma, Li−Li Xu, Ling Jie Yuan, Xi Yang, Rui Wu, Shu Min Bao, Yi Li Chen, Hong Liang Duan, Luo Fang, Hua Jun Zhao, Zha Jun Zhan

研究成果: Article同行評審

摘要

Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure−activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.

原文English
頁(從 - 到)13089-13105
頁數17
期刊Journal of Medicinal Chemistry
67
發行號15
DOIs
出版狀態Published - 8 8月 2024

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