一种新型的1,2,5-硒二唑衍生物的合成、鉴定和表征克服多药耐药的微管靶向剂

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Farhat Firdous, Syed Usama Bin Farrukh, Muhammad Furqan, Sana Shaukat, Salman Fozail, Sebastian Öther-Gee Pohl, Aslıhan Bastem Akan, Kevin B. Myant, Fatimah Alahmari, Abdul-Hamid Emwas, Mariusz Jaremko, Ghayoor Abbas, Rahman Shah Zaib Saleem, Amir Faisal
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引用次数: 0

摘要

微管对各种细胞过程至关重要,包括细胞分裂,它们形成高度动态的纺锤体纤维,用于染色体排列和分离。通过微管靶向药物(mta)干扰微管动力学可阻断有丝分裂的进程,最终导致细胞凋亡。尽管mta已被有效地用作各种癌症的一线治疗方法,但多药耐药(MDR)往往限制了它们的有效性。硒二唑是一类具有抗癌活性的有机硒化合物。合成了18个新的1,2,5-硒二唑衍生物,其中3个(9d, 9f和9i)对HCT116结直肠癌细胞具有较强的抗增殖活性。用最有效的化合物之一9f (SSE1706)处理细胞(GI50值为1.89±0.99µM),破坏有丝分裂纺锤体形成,导致G2/M停滞。在基于细胞的实验中,9f抑制微管聚合,长期使用9f稳定p53并诱导细胞凋亡。此外,9f还能有效抑制小鼠和人类结肠癌衍生类器官的生长。最后,9f对过表达MDR-1的KB-V1细胞表现出有效的抗增殖活性,突出了其克服MDR的潜力。这些发现表明9f是进一步优化研究的先导化合物,特别是针对MDR。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Synthesis, Identification, and Characterization of a Novel 1,2,5-Selenadiazole Derivative as a Microtubule Targeting Agent That Overcomes Multidrug Resistance

Microtubules are crucial for various cellular processes, including cell division, where they form highly dynamic spindle fibers for chromosomal alignment and segregation. Interference with microtubule dynamics through microtubule targeting agents (MTAs) blocks progression through mitosis, ultimately resulting in apoptosis. Although MTAs have been effectively used as a frontline treatment for various cancers, multidrug resistance (MDR) often limits their effectiveness. This study focuses on selenadiazoles, a group of organic selenium compounds with anticancer activities. Eighteen novel 1,2,5-selenadiazole derivatives were synthesized, three of which (9d, 9f, and 9i) showed potent antiproliferative activity in HCT116 colorectal cancer cells. Treatment of cells with 9f (SSE1706), one of the most potent compounds (GI50 value of 1.89 ± 0.99 µM), disrupted mitotic spindle formation, leading to G2/M arrest. 9f inhibited microtubule polymerization in cell-based assays, and long-term treatment with 9f stabilized p53 and induced apoptosis. Moreover, 9f effectively inhibited the growth of mouse and human colon cancer-derived organoids. Finally, 9f exhibited potent antiproliferative activity against MDR-1 overexpressing KB-V1 cells, highlighting its potential to overcome MDR. These findings suggest 9f as a lead compound for further optimization studies, particularly targeting MDR.

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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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