Design, synthesis and biological evaluation of plant-derived miliusol derivatives achieve TNBC profound regression in vivo.

Autor: Zhao X; State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; School of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China., Cheng X; School of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China., Liu Z; School of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China., Chen W; School of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China; School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518060, China., Hao W; School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518060, China., Ma S; School of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China., Zhang J; School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518060, China. Electronic address: zhangjin1989@szu.edu.cn., Huang W; State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. Electronic address: huangwei@cdutcm.edu.cn., Yao D; School of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China. Electronic address: yaodahong@sztu.edu.cn.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Dec 05; Vol. 279, pp. 116882. Date of Electronic Publication: 2024 Sep 18.
DOI: 10.1016/j.ejmech.2024.116882
Abstrakt: Triple-negative breast cancer has become a major problem in clinical treatment due to its high heterogeneity, and Plant-derived drug discovery has been the focus of attention for novel anti-tumor therapeutics. In this study, Miliusol, a natural product isolated from the rarely reported plant Miliusa tenuistipitata, was identified as the lead compound, and 25 miliusol derivatives were designed and synthesized under antiproliferative activity guidance. The results revealed that ZMF-24 was demonstrated to have potent anti-TNBC proliferation with IC 50 values of 0.22 μM and 0.44 μM in BT-549 cells and MDA-MB-231 cells respectively with low cytotoxicity to MCF10A cells, and could significantly downregulate proliferation and migration markers. Through RNAseq analysis, molecular docking and CETSA experiment, we found that ZMF-24 could inhibit Eukaryotic translation initiation factor 3 subunit D (EIF3D) that further disrupted the energy supply of TNBC by inhibiting glycolysis, induced profound TNBC apoptosis by stimulating persistent ER stress. Importantly, ZMF-24 exhibited remarkable anti-proliferation and anti-metastasis potential in nude mice xenograft TNBC model without obvious toxicity. Collectively, the findings demonstrate ZMF-24 has significant potential as a potent chemotherapy agent against triple-negative breast cancer.
Competing Interests: Declaration of competing interest The author declare that they have no conflict of Interests.
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Databáze: MEDLINE
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