异喹啉
化学
三阴性乳腺癌
生物碱
乳腺癌
立体化学
癌症研究
癌症
药理学
内科学
医学
生物
作者
Feng-Yang Wang,Liang-Mei Yang,Shanshan Wang,Hui Lu,Xusheng Wang,Yuan Liu,Wen‐Xiu Ni,Hong Liang,Ke-Bin Huang
标识
DOI:10.1021/acs.jmedchem.4c00285
摘要
The development and optimization of metal-based anticancer drugs with novel cytotoxic mechanisms have emerged as key strategies to overcome chemotherapeutic resistance and side effects. Agents that simultaneously induce ferroptosis and autophagic death have received extensive attention as potential modalities for cancer therapy. However, only a limited set of drugs or treatment modalities can synergistically induce ferroptosis and autophagic tumor cell death. In this work, we designed and synthesized four new cycloplatinated (II) complexes harboring an isoquinoline alkaloid C∧N ligand. On screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased resistance factors, and improved anticancer activity compared to cisplatin. Furthermore, Pt-3, which we demonstrate can initiate potent ferritinophagy-dependent ferroptosis, exhibits less toxic and better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug development in cancer treatment.
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