Tan Huayuan, Zhang Guanglong, Xu Chenlu, Lei Xue, Chen Jiayi, Long Haitao, Qiu Xuemei, Wang Wenhang, Zhou Yue, Chen Danping, Li Chengpeng, Li Zhurui, Wang Zhenchao
College of Pharmacy, Guizhou University, Guiyang, 550025, China.
National Key Laboratory of Green Pesticide, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals of Guizhou University, Guiyang, 550025, China.
Mol Divers. 2025 Jun;29(3):1983-2000. doi: 10.1007/s11030-024-10954-1. Epub 2024 Aug 7.
Induction of autophagic death in cancer cells is one of the promising strategies for the development of anti-cancer therapeutics. In the present study, we designed and synthesized a series of isatin Schiff base derivatives containing thioether structures. After discovering the highly active target compound H13 (IC = 4.83 μM) based on in vitro antiproliferation, we also found it had a high safety against normal cells HEK293 with CC of 69.01 μM, indicating a sufficient therapeutic window. In addition, to provide reference for subsequent studies, a model was successfully constructed by Sybyl software. Preliminary mechanistic studies suggested that H13-induced apoptosis may be closely related to ROS accumulation and mitochondrial dysfunction. Subsequent studies revealed that H13 inhibited cell proliferation by inducing cellular autophagy mainly through blocking signal of the PI3K/AKT/mTOR pathway. Altogether, these results suggested that H13 was potentially valuable as a lead compound.
诱导癌细胞自噬性死亡是开发抗癌治疗药物的有前景的策略之一。在本研究中，我们设计并合成了一系列含有硫醚结构的异吲哚酮席夫碱衍生物。基于体外抗增殖作用发现高活性目标化合物H13（IC = 4.83 μM）后，我们还发现它对正常细胞HEK293具有高安全性，CC为69.01 μM，表明有足够的治疗窗口。此外，为后续研究提供参考，通过Sybyl软件成功构建了一个模型。初步机制研究表明，H13诱导的细胞凋亡可能与ROS积累和线粒体功能障碍密切相关。后续研究表明，H13主要通过阻断PI3K/AKT/mTOR信号通路诱导细胞自噬来抑制细胞增殖。总之，这些结果表明H13作为先导化合物具有潜在价值。
