Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250012, China.
Central Laboratory, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250012, China.
Eur J Med Chem. 2023 Dec 15;262:115870. doi: 10.1016/j.ejmech.2023.115870. Epub 2023 Oct 18.
Taking a previously discovered indazole derivative 1 as a lead, systematic structural modifications were performed with an indazole core at the 1- and 6-positions to improve its aqueous solubility. Among the designed indazole derivatives, 6-methylpyridin-3-yl indazole derivative 8l and 1H-indol-4-yl indazole derivative 8m exhibited high potency in the low nanomolar range against A549, Huh-7, and T24 cancer cells, including Taxol-resistant variant cells (A549/Tax). As a hydrochloride salt, 8l exhibited much improved aqueous solubility, and its log P value fell into a favorable range. In mechanistic studies, 8l impeded tubulin polymerization through interacting with the colchicine site, resulting in cell cycle arrest and cellular apoptosis. In addition, compared to lead compound 1, 8l reduced cell migration and led to more potent inhibition of tumor growth in vivo without apparent toxicity. In summary, indazole derivative 8l could work as a potential anticancer agent and deserves further investigation for cancer therapy.
以先前发现的吲唑衍生物 1 为先导化合物，对吲唑核心的 1-位和 6-位进行了系统的结构修饰，以提高其水溶性。在所设计的吲唑衍生物中，6-甲基吡啶-3-基吲唑衍生物 8l 和 1H-吲哚-4-基吲唑衍生物 8m 对 A549、Huh-7 和 T24 癌细胞（包括紫杉醇耐药变体细胞 A549/Tax）表现出高活性，处于纳摩尔低浓度范围内。作为盐酸盐，8l 表现出明显提高的水溶性，其 log P 值落入有利范围。在机制研究中，8l 通过与秋水仙碱结合部位相互作用来抑制微管蛋白聚合，导致细胞周期停滞和细胞凋亡。此外，与先导化合物 1 相比，8l 减少了细胞迁移，并在体内更有效地抑制肿瘤生长，而没有明显的毒性。综上所述，吲唑衍生物 8l 可能成为一种有潜力的抗癌药物，值得进一步研究用于癌症治疗。
