晚期转移性结直肠癌是临床癌症治疗中的挑战。我们先前的研究表明，一种代表性的氟代基取代吲哚-甲酰苯梦灵（FC116）通过靶向微管，在多种体外和体内小鼠模型中表现出对结直肠癌非常强效的活性。然而，仍存在许多问题，如低剂量耐受性和对大脑和结肠的高毒性，低溶解度不适合静脉注射（i.v.）等，这些限制了进一步的开发。因此，我们通过基于构效关系的设计策略，开发了两个系列的FC116衍生物，探索4-甲氧基苯基分子中它的构效结构。其中，FC11619保持了氨基末端，在体外低纳摩尔级别内表现出对HCT-116结直肠癌的细胞毒性。该化合物可通过调控细胞周期素B1表达，在G2/M期阻滞细胞，产生过多的活性氧物种（ROS），并以靶向微管的方式作用于肿瘤细胞。在体内，FC11619显著抑制了肿瘤生长，5和10 mg/kg/d（i.v., 21 d）剂量下，其抑制率分别达到了65.3％和73.4％，远优于7 mg/kg的紫杉烷（Taxol）54.1％的抑制率。此外，与FC116（仅3 mg/kg耐受，腹腔注射，i.p.）相比，该化合物在体内耐受性更好，没有主要器官相关的毒性，特别是没有明显的变性神经元、肠梗阻等，这些毒性通常出现在临床紫杉烷标准治疗中。综上，4-氨基取代苯基吲哚-甲酰苯梦灵是一种有望在结直肠癌化疗领域进一步开发的主导化合物。 本文版权所有 © 2023 Elsevier Inc。

Advanced metastatic colorectal cancers (CRCs) are regarded as a challenge in clinical cancer therapy. Our previous studies have demonstrated that a representative fluoro-substituted indole-chalcone (FC116), was obtained to display highly potent activity against CRC using multiple in vitro and in vivo mouse models by targeting microtubules. However, several problems, such as low dose tolerance and highly toxic to the brain and colon, low solubility unsuitable for intravenous (i.v.) administration, are still existed and limit further development. Herein, we developed two series of FC116 derivatives on the 4-methoxyphenyl group by a structure-based design strategy. Among them, FC11619 with an amino terminus maintained the in vitro cytotoxicity against HCT-116 CRC in a low nanomolar range. This compound could induce G2/M phase arrest via regulating cyclin B1 expression, produce excess reactive oxygen species (ROS), and target tubulin in CRC cells. In vivo, FC11619 significantly suppressed tumor growth, achieving 65.3 and 73.4 % at doses of 5 and 10 mg/kg/d (i.v., 21 d), which were much better than 54.1% of Taxol at 7 mg/kg. In addition, this compound showed better in vivo tolerance compared to that of FC116 (only 3 mg/kg tolerance, intraperitoneal, i.p.), and no major organ-related toxicity, especially no apparent degenerated neurons, intestinal obstruction in clinical Taxol standard therapy. Taken together, the 4-amino-substitutedphenyl indole-chalcones represent lead compounds as chemotherapy of CRC for further drug development in this field.Copyright © 2023 Elsevier Inc. All rights reserved.