Synthesis, Identification, and Characterization of a Novel 1,2,5-Selenadiazole Derivative as a Microtubule Targeting Agent That Overcomes Multidrug Resistance
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
Abstract
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.
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.