Design, synthesis and biological evaluation of novel podophyllotoxin derivatives as tubulin-targeting anticancer agents.

IF 3.9 3区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY
Pharmaceutical Biology Pub Date : 2024-12-01 Epub Date: 2024-02-23 DOI:10.1080/13880209.2024.2318350
Yujin Guo, Beibei Chen, Jinxiu Guo, Pei Jiang, Jianhua Wang, Wenxue Sun
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引用次数: 0

Abstract

Context: Podophyllotoxin (PPT) derivatives, used in cancer therapy, require development toward enhanced efficacy and reduced toxicity.

Objective: This study synthesizes PPT derivatives to assess their anticancer activities.

Materials and methods: Compounds E1-E16 antiproliferative activity was tested against four human cancer cell lines (H446, MCF-7, HeLa, A549) and two normal cell lines (L02, BEAS-2B) using the CCK-8 assay. The effects of compound E5 on A549 cell growth were evaluated through molecular docking, in vitro assays (flow cytometry, wound healing, Transwell, colony formation, Western blot), and in vivo tests in female BALB/c nude mice treated with E5 (2 and 4 mg/kg). E5 (4 mg/kg) significantly reduced xenograft tumor growth compared to the DMSO control group.

Results: Among the 16 PPT derivatives tested for cytotoxicity, E5 exhibited potent effects against A549 cells (IC50: 0.35 ± 0.13 µM) and exceeded the reference drugs PPT and etoposide to inhibit the growth of xenograft tumours. E5-induced cell cycle arrest in the S and G2/M phases accelerated tubulin depolymerization and triggered apoptosis and mitochondrial depolarization while regulating the expression of apoptosis-related proteins and effectively inhibited cell migration and invasion, suggesting a potential to limit metastasis. Molecular docking showed binding of E5 to tubulin at the colchicine site and to Akt, with a consequent down-regulation of PI3K/Akt pathway proteins.

Discussion and conclusions: This research lays the groundwork for advancing cancer treatment through developing and using PPT derivatives. The encouraging results associated with E5 call for extended research and clinical validation, leading to novel and more effective cancer therapies.

作为微管蛋白靶向抗癌剂的新型荚叶素衍生物的设计、合成和生物学评价。
背景:用于癌症治疗的鬼臼毒素(PPT)衍生物需要向提高疗效和降低毒性的方向发展:本研究合成了 PPT 衍生物,以评估其抗癌活性:采用 CCK-8 检测法测试了化合物 E1-E16 对四种人类癌细胞株(H446、MCF-7、HeLa、A549)和两种正常细胞株(L02、BEAS-2B)的抗增殖活性。化合物 E5 对 A549 细胞生长的影响是通过分子对接、体外试验(流式细胞仪、伤口愈合、Transwell、菌落形成、Western 印迹)以及用 E5(2 毫克/千克和 4 毫克/千克)处理雌性 BALB/c 裸鼠的体内试验来评估的。与二甲基亚砜对照组相比,E5(4 毫克/千克)能明显减少异种移植肿瘤的生长:结果:在进行细胞毒性测试的 16 种 PPT 衍生物中,E5 对 A549 细胞具有强效作用(IC50:0.35 ± 0.13 µM),在抑制异种移植瘤生长方面超过了参考药物 PPT 和依托泊苷。E5 诱导的细胞周期停滞在 S 期和 G2/M 期,加速了微管蛋白的解聚,触发了细胞凋亡和线粒体去极化,同时调节了细胞凋亡相关蛋白的表达,有效抑制了细胞的迁移和侵袭,表明其具有限制转移的潜力。分子对接显示,E5与秋水仙碱位点的小管蛋白和Akt结合,从而下调PI3K/Akt通路蛋白:这项研究为通过开发和使用 PPT 衍生物推进癌症治疗奠定了基础。与 E5 相关的令人鼓舞的结果要求进行更广泛的研究和临床验证,从而开发出更有效的新型癌症疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Pharmaceutical Biology
Pharmaceutical Biology 医学-药学
CiteScore
6.70
自引率
2.60%
发文量
191
审稿时长
1 months
期刊介绍: Pharmaceutical Biology will publish manuscripts describing the discovery, methods for discovery, description, analysis characterization, and production/isolation (including sources and surveys) of biologically-active chemicals or other substances, drugs, pharmaceutical products, or preparations utilized in systems of traditional medicine. Topics may generally encompass any facet of natural product research related to pharmaceutical biology. Papers dealing with agents or topics related to natural product drugs are also appropriate (e.g., semi-synthetic derivatives). Manuscripts will be published as reviews, perspectives, regular research articles, and short communications. The primary criteria for acceptance and publication are scientific rigor and potential to advance the field.
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