Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Eur J Med Chem. 2022 Aug 5;238:114450. doi: 10.1016/j.ejmech.2022.114450. Epub 2022 May 11.
Head and neck squamous cell carcinoma (HNSCC) is a lethal disease with a terrible prognosis, accounting for more than 900,000 new cases and 500,000 deaths each year, nevertheless, its pharmacotherapy is rather limited. Parbendazole was previously identified as a potential HNSCC therapy candidate in our research. Herein, we report the discovery of two series of parbendazole derivatives as tubulin inhibitors. Structure-activity relationship (SAR) analyses led to the discovery of compound 9q with the best pharmacological activities and pharmacokinetic properties. This compound exhibited reasonable inhibition activity on cell proliferation (HN6, CAL-27, Fadu) and tubulin polymerization, induced cell apoptosis, blocked cell cycle and suppressed cell migration and invasion. Compound 9q also displayed low toxicity and a favorable therapeutic effect on a xenograft tumor, indicating that it is a promising starting point for further research.
头颈部鳞状细胞癌（HNSCC）是一种致命疾病，预后极差，每年有超过 90 万例新发病例和 50 万例死亡病例，但目前的药物治疗选择非常有限。在我们的研究中，帕苯达唑最初被确定为一种有潜力的 HNSCC 治疗候选药物。在此，我们报告了两类作为微管蛋白抑制剂的帕苯达唑衍生物的发现。结构-活性关系（SAR）分析导致发现了具有最佳药理活性和药代动力学特性的化合物 9q。该化合物对细胞增殖（HN6、CAL-27、Fadu）和微管蛋白聚合具有合理的抑制活性，诱导细胞凋亡，阻断细胞周期，抑制细胞迁移和侵袭。化合物 9q 还表现出较低的毒性和对异种移植肿瘤的良好治疗效果，表明它是进一步研究的有前途的起点。
