靶向K562肿瘤细胞的1,3,4-噁二唑衍生物的合成、抗癌活性评价及初步作用机制研究

doi:10.6023/cjoc202601044

有机化学

研究论文

靶向K562肿瘤细胞的1,3,4-噁二唑衍生物的合成、抗癌活性评价及初步作用机制研究

吴越友^a, 何丹丹^a, 冯念林^a, 张依^a, 刘丹丹^a, 周玥^a, 李晨晨^a,*, 王贞超^a,b,*

^a贵州大学药学院,贵州贵阳 550025;
^b绿色农药全国重点实验室,绿色农药与农业生物工程教育部重点实验室,贵州大学精细化工研究开发中心,贵州贵阳 550025

收稿日期:2026-03-24 修回日期:2026-05-26
基金资助:
国家自然科学基金（项目编号：32360689）、贵州省优秀青年学者项目基金（项目编号：GCC[2023]072）、国家重点研发计划（项目编号：2023YFD1400400）以及贵州省基础研究计划（自然科学）青年引导项目（项目编号：QN[2025]010、QN[2025]009）.

Synthesis, anticancer evaluation, and preliminary mechanism study of 1,3,4-oxadiazole derivatives targeting K562 tumor cells

Wu Yueyou^a, He Dandan^a, Feng Nianlin^a, Zhang Yi^a, Liu Dandan^a, Zhou Yue^a, Li Chenchen^a,*, Wang Zhenchao^a,b,*

^aSchool of Pharmaceutical Sciences, Guizhou University, Guiyang, Guizhou 550025;
^bState Key Laboratory of Green Pesticides, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals of Guizhou University, Guiyang, Guizhou 550025

Received:2026-03-24 Revised:2026-05-26
Contact: * E-mail: licc@gzu.edu.cn,zcwang@gzu.edu.cn
Supported by:
We gratefully acknowledge financial support from the National Natural Science Foundation of China (Grant No. 32360689), the Guizhou Provincial Foundation for Excellent Scholars Program (Project No. GCC[2023]072), the National Key Research and Development Program of China (Grant No. 2023YFD1400400), and the Youth Guidance Project of the Guizhou Provincial Basic Research Program (Natural Science) (Grant No. QN[2025]010, QN[2025]009).

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摘要/Abstract

慢性粒细胞白血病（CML）是一种以髓系细胞异常增殖为特征的血液系统恶性肿瘤。由于常规酪氨酸激酶抑制剂耐药性的出现,开发新型抗肿瘤药物势在必行。本研究基于具有抗肿瘤潜力的吲哚、1,3,4-噁二唑和苯磺酰胺药效团,设计合成了30个新型杂化衍生物,旨在提升活性和选择性。其中化合物XL-10对CML K562细胞展现出强效抗增殖作用（IC₅₀=6.69 ± 0.35 μM）。机制研究表明,XL-10通过打破氧化还原稳态诱导K562细胞凋亡,其主要表现为活性氧（ROS）水平升高和线粒体膜电位降低;流式细胞分析显示该化合物通过调控Cyclin B1及CDK1等关键周期蛋白将细胞阻滞于G2/M期;蛋白质组学和Western blot实验证实其对MAPK和PI3K-AKT信号通路的调节作用。该研究系统阐明了XL-10的抗肿瘤作用机制,突显其作为靶向CML治疗先导化合物的开发潜力。

关键词: K562细胞、抗癌活性、含氮杂环、慢性髓性白血病、1,3,4-噁二唑

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by abnormal myeloid cell proliferation, and the emergence of drug resistance to conventional tyrosine kinase inhibitors necessitates novel antitumor agents. In this study, we synthesized 30 novel hybrid derivatives incorporating indole, 1,3,4-oxadiazole, and benzenesulfonamide scaffolds—pharmacophores recognized for antitumor potential—aiming to enhance activity and selectivity. Among these compounds, XL-10 demonstrated potent antiproliferative effects against CML K562 cells, exhibiting an IC₅₀ value of 6.69 ± 0.35 μM. Mechanistic investigations revealed that XL-10 induces apoptosis in K562 cells by disrupting redox homeostasis, as evidenced by elevated reactive oxygen species (ROS) levels and reduced mitochondrial membrane potential. Flow cytometry analysis indicated that XL-10 arrests K562 cells at the G2/M phase through regulation of key cell cycle proteins including Cyclin B1 and CDK1, while Western blot assays confirmed its modulation of the MAPK and PI3K-AKT signaling pathways. These findings elucidate the antitumor mechanisms of XL-10 and highlight its potential as a promising lead compound for the development of targeted CML therapies.

Key words: K562 cells, anticancer activity, nitrogen-containing heterocycles, chronic myeloid leukemia, 1,3,4-oxadiazole

引用此文

吴越友, 何丹丹, 冯念林, 张依, 刘丹丹, 周玥, 李晨晨, 王贞超. 靶向K562肿瘤细胞的1,3,4-噁二唑衍生物的合成、抗癌活性评价及初步作用机制研究[J]. 有机化学, doi: 10.6023/cjoc202601044.

Wu Yueyou, He Dandan, Feng Nianlin, Zhang Yi, Liu Dandan, Zhou Yue, Li Chenchen, Wang Zhenchao. Synthesis, anticancer evaluation, and preliminary mechanism study of 1,3,4-oxadiazole derivatives targeting K562 tumor cells[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202601044.

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靶向K562肿瘤细胞的1,3,4-噁二唑衍生物的合成、抗癌活性评价及初步作用机制研究

Synthesis, anticancer evaluation, and preliminary mechanism study of 1,3,4-oxadiazole derivatives targeting K562 tumor cells

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