2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel (E)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl) derivatives as potent STAT3-targeting anticolorectal cancer agents

Design, synthesis, and biological evaluation of novel (E)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl) derivatives as potent STAT3-targeting anticolorectal cancer agents

  • Bioorg Chem. 2024 Dec:153:107955. doi: 10.1016/j.bioorg.2024.107955.
Weiqing Jiang 1,  Pingxian Liu 1,  Zhangxun Zhao 1,  Dongmei Fan 1,  Xinlian He 2,  Yunhan Jiang 3,  Tao Yang 4
Affiliations

Affiliations

  • 1 Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: jiangyunhan@wchscu.cn.
  • 4 Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yangtao@wchscu.cn.
PMID: 39577151 DOI: 10.1016/j.bioorg.2024.107955
Abstract

Dysregulation of signal transducer and activator of transcription 3 (STAT3) is implicated in the pathogenesis of various cancers, underscoring its potential as a Cancer therapeutic target. In this work, we designed and synthesized a novel series of (E)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl) derivatives and evaluated their anti-proliferative effects on tumour cells. Among these derivatives, NW16 exhibited remarkable antiproliferative activity against HCT116 cells, with an IC50 value of 0.28 μM, and exhibited dose- and time-dependent inhibition of the JAK/STAT3 signalling pathway. In addition, NW16 induced Reactive Oxygen Species (ROS) production, which subsequently suppressed the ROS-dependent PI3K/Akt pathway and enhanced its antitumour efficacy. In vivo studies confirmed significant tumour-suppressive effects upon oral administration of NW16 along with favourable tolerability in a colorectal Cancer xenograft model. These results indicate that NW16 could be a promising candidate for developing targeted therapy for colorectal Cancer because of its multifaceted mechanism.

Keywords

Colorectal cancer; Hybridization; Napabucasin; ROS; STAT3 inhibitors.

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