Synthesis and characterization of bis-amide SSE1917 as a microtubule-stabilizing anticancer agent
Synthesis and characterization of bis-amide SSE1917 as a microtubule-stabilizing anticancer agent
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DOI：
10.1016/j.bioorg.2023.107094
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发表时间：
2024-01-09
影响因子：
5.1
通讯作者：
Saleem，Rahman Shah Zaib
中科院分区：
文献类型：
--
作者：
Iqbal，Sana;Firdous，Farhat;Saleem，Rahman Shah Zaib
微管动力学对于细胞分裂过程中纺锤体组装和染色体分离至关重要。对细胞中微管动力学的药理抑制会导致有丝分裂延长，从而导致细胞凋亡，这是一种广泛用于治疗不同类型癌症的方法。本研究报告了 32 种新型双酰胺 (SSE1901-SSE1932) 的合成及其抗增殖活性的评估。N-(1-氧代-3-苯基-1-(苯氨基)丙-2-基)苯甲酰胺 (SSE1917) 在 HCT116 中表现出最有效的活性，GI50 值为 0.331 ± 0.01 µM结肠直肠细胞中的浓度为 0.48 ± 0.27 µM，BT-549 乳腺癌细胞中的浓度为 0.48 ± 0.27 µM。SSE1917 在生化和细胞测定中稳定微管，在对接研究中与紫杉醇位点结合，并导致细胞异常有丝分裂和 G2/M 期停滞。用该化合物长时间处理细胞会增加 p53 的表达并引发细胞凋亡。此外，SSE1917 抑制小鼠和患者来源的人类结肠癌类器官的生长，凸显了其作为抗癌药物的潜在治疗价值。
Microtubule dynamics are critical for spindle assembly and chromosome segregation during cell division. Pharmacological inhibition of microtubule dynamics in cells causes prolonged mitotic arrest, resulting in apoptosis, an approach extensively employed in treating different types of cancers. The present study reports the synthesis of thirty-two novel bis-amides(SSE1901-SSE1932)and the evaluation of their antiproliferative activities.N-(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)benzamide (SSE1917)exhibited the most potent activity with GI50values of 0.331 ± 0.01 µM in HCT116 colorectal and 0.48 ± 0.27 µM in BT-549 breast cancer cells.SSE1917stabilized microtubules in biochemical and cellular assays, bound to taxol site in docking studies, and caused aberrant mitosis and G2/M arrest in cells. Prolonged treatment of cells with the compound increased p53 expression and triggered apoptotic cell death. Furthermore,SSE1917suppressed the growth of both mouse and patient-derived human colon cancer organoids, highlighting its potential therapeutic value as an anticancer agent.