Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
Eur J Med Chem. 2023 Sep 5;257:115540. doi: 10.1016/j.ejmech.2023.115540. Epub 2023 Jun 2.
Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract with high morbidity and mortality. Our previous studies have demonstrated that indole-chalcone-based compounds targeting tubulin displayed potential cytotoxicity to CRC cells. Herein, three new series of derivatives were systematically designed and synthesized to explore their structure-activity relationship (SAR) against CRC based on prior research. Among them, a representative fluorine-containing analog (FC116) exerted superior efficacy on HCT116 (IC = 4.52 nM) and CT26 (IC = 18.69 nM) cell lines, and HCT116-xenograft mice with tumor growth inhibition rate of 65.96% (3 mg/kg). Of note, FC116 could also suppress the growth of organoid models (IC = 1.8-2.5 nM) and showed adenoma number inhibition rate of 76.25% at the dose of 3 mg/kg in APC mice. In terms of mechanism, FC116 could induce endoplasmic reticulum (ER) stress to produce excess reactive oxygen species (ROS), leading to mitochondrial damage to promote the apoptosis of CRC cells by targeting microtubules. Our results support that indole-chalcone compounds are promising tubulin inhibitors and highlight the potential of FC116 to combat CRC.
结直肠癌（CRC）是一种常见的胃肠道恶性肿瘤，具有较高的发病率和死亡率。我们之前的研究表明，以吲哚查尔酮为基础的靶向微管的化合物对 CRC 细胞具有潜在的细胞毒性。在此基础上，我们系统地设计并合成了三个新系列的衍生物，以探索其针对 CRC 的构效关系（SAR）。其中，一个代表性的含氟类似物（FC116）对 HCT116（IC=4.52 nM）和 CT26（IC=18.69 nM）细胞系表现出优异的疗效，在 HCT116 荷瘤小鼠中肿瘤生长抑制率为 65.96%（3mg/kg）。值得注意的是，FC116 还可以抑制类器官模型的生长（IC=1.8-2.5 nM），并在 APC 小鼠中以 3mg/kg 的剂量抑制腺瘤数量，抑制率为 76.25%。在机制方面，FC116 可以诱导内质网（ER）应激产生过多的活性氧（ROS），导致线粒体损伤，通过靶向微管促进 CRC 细胞凋亡。我们的研究结果表明，吲哚查尔酮类化合物是有前途的微管抑制剂，并强调了 FC116 治疗 CRC 的潜力。
