发现新型 4-三氟甲基-2-苯胺喹啉衍生物作为靶向 SGK1 的潜在抗癌剂。

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED Molecular Diversity Pub Date : 2024-08-09 DOI:10.1007/s11030-024-10951-4
Guangcan Xu, Lanlan Li, Mengfan Lv, Cheng Li, Jia Yu, Xiaoping Zeng, Xueling Meng, Gang Yu, Kun Liu, Sha Cheng, Heng Luo, Bixue Xu
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引用次数: 0

摘要

鉴于开发更有效的抗癌药物的迫切需要,我们设计、合成了一系列新型化合物,并通过药效杂交策略对这些化合物进行了生物学评价。在对目标化合物的体外抗癌特性进行评估后发现,化合物 8b 在喹啉骨架的 2 位上含有(4-(哌嗪-1-基)苯基)氨基取代,通过诱导细胞凋亡和细胞周期停滞,对四种癌细胞株显示出卓越的疗效。在对 PC3 异种移植小鼠模型进行研究后发现,化合物 8b 具有显著的抗癌功效,同时毒性极低。此外,对 217 激酶面板的分析将 SGK1 确定为该化合物类具有抗癌能力的潜在靶点。分子对接分析和细胞热转移实验进一步验证了这一发现。总之,我们的研究结果表明,化合物 8b 可以作为先导化合物,用于开发靶向 SGK1 的抗癌药物。
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Discovery of novel 4-trifluoromethyl-2-anilinoquinoline derivatives as potential anti-cancer agents targeting SGK1.

Given the critical necessity for the development of more potent anti-cancer drugs, a series of novel compounds incorporating trifluoromethyl groups within the privileged 2-anilinoquinoline scaffold was designed, synthesized, and subjected to biological evaluation through a pharmacophore hybridization strategy. Upon evaluating the in vitro anti-cancer characteristics of the target compounds, it became clear that compound 8b, which contains a (4-(piperazin-1-yl)phenyl)amino substitution at the 2-position of the quinoline skeleton, displayed superior efficacy against four cancer cell lines by inducing apoptosis and cell cycle arrest. Following research conducted in a PC3 xenograft mouse model, it was found that compound 8b exhibited significant anti-cancer efficacy while demonstrating minimal toxicity. Additionally, the analysis of a 217-kinase panel pinpointed SGK1 as a potential target for this compound class with anti-cancer capabilities. This finding was further verified through molecular docking analysis and cellular thermal shift assays. To conclude, our results emphasize that compound 8b can be used as a lead compound for the development of anti-cancer drugs that target SGK1.

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来源期刊
Molecular Diversity
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;
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