Synthesis of novel 4-substituted isatin Schiff base derivatives as potential autophagy inducers and evaluation of their antitumour activity.

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2024-08-07 DOI:10.1007/s11030-024-10954-1

Huayuan Tan, Guanglong Zhang, Chenlu Xu, Xue Lei, Jiayi Chen, Haitao Long, Xuemei Qiu, Wenhang Wang, Yue Zhou, Danping Chen, Chengpeng Li, Zhurui Li, Zhenchao Wang

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Abstract

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 (IC₅₀ = 4.83 μM) based on in vitro antiproliferation, we also found it had a high safety against normal cells HEK293 with CC₅₀ 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.

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合成新型 4-取代靛红席夫碱衍生物作为潜在的自噬诱导剂并评估其抗肿瘤活性。

诱导癌细胞自噬死亡是开发抗癌疗法的一种有前途的策略。在本研究中，我们设计并合成了一系列含有硫醚结构的isatin席夫碱衍生物。在发现了体外抗增殖的高活性靶向化合物 H13（IC50 = 4.83 μM）之后，我们还发现它对正常细胞 HEK293 具有很高的安全性，CC50 为 69.01 μM，这表明它具有足够的治疗窗口期。此外，为了给后续研究提供参考，我们还利用 Sybyl 软件成功构建了一个模型。初步机理研究表明，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。随后的研究发现，H13主要通过阻断PI3K/AKT/mTOR通路信号诱导细胞自噬，从而抑制细胞增殖。总之，这些结果表明，H13 是一种有潜在价值的先导化合物。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;