Design, Synthesis, and Biological Evaluation of SSE1806, a Microtubule Destabilizer That Overcomes Multidrug Resistance
Design, Synthesis, and Biological Evaluation of SSE1806, a Microtubule Destabilizer That Overcomes Multidrug Resistance
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克服多药耐药性的微管去稳定剂 SSE1806 的设计、合成和生物学评价
DOI：
10.1021/acsmedchemlett.3c00258
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发表时间：
2023
影响因子：
4.2
通讯作者：
Firdous F
中科院分区：
文献类型：
--
作者：
Firdous F
微管是在细胞分裂期间形成纺锤体纤维的动态结构;微管动力学的药理学抑制使细胞停止有丝分裂，导致细胞凋亡，并且它们已被广泛用于治疗各种癌症。然而，这类药物的疗效往往受到多药耐药性的限制。本研究合成了30个新型抗有丝分裂活性化合物鬼臼毒素衍生物，并对其抗增殖活性进行了评价。化合物SSE 1806在不同来源的癌细胞系中表现出最有效的抗增殖活性，GI 50值范围为1.29 ± 0.01至21.15 ± 2.1 μM;它直接抑制微管聚合，引起异常有丝分裂和G2/M期阻滞。用SSE 1806延长治疗增加了p53表达，诱导了单层培养物中的细胞死亡，并减少了小鼠和患者来源的人结肠癌类器官的生长。重要的是，SSE 1806克服了过表达MDR-1的细胞系中的多药耐药性。因此，SSE 1806代表了一种潜在的抗癌剂，可以克服多药耐药性。
Microtubules are dynamic structures that form spindle fibers during cell division; pharmacological inhibition of microtubule dynamics arrests cells in mitosis, leading to apoptosis, and they have been extensively used to treat various cancers. However, the efficacy of such drugs is often limited by multidrug resistance. This study synthesized and evaluated 30 novel derivatives of podophyllotoxin, a natural antimitotic compound, for their antiproliferative activities. Compound SSE1806 exhibited the most potent antiproliferative activity with GI50values ranging from 1.29 ± 0.01 to 21.15 ± 2.1 μM in cancer cell lines of different origins; it directly inhibited microtubule polymerization, causing aberrant mitosis and G2/M arrest. Prolonged treatment with SSE1806 increased p53 expression, induced cell death in monolayer cultures, and reduced the growth of mouse- and patient-derived human colon cancer organoids. Importantly, SSE1806 overcame multidrug resistance in a cell line overexpressing MDR-1. Thus, SSE1806 represents a potential anticancer agent that can overcome multidrug resistance.