2. Academic Validation
  3. Novel E-F ring derivatives of aconitine scaffold as potent Hsp90 inhibitors for the treatment of colorectal cancer

Novel E-F ring derivatives of aconitine scaffold as potent Hsp90 inhibitors for the treatment of colorectal cancer

  • Eur J Med Chem. 2025 Oct 15:296:117895. doi: 10.1016/j.ejmech.2025.117895.
Yi Zhang 1,  Yan-Ping Wang 2,  Shuai Guo 2,  Ting-Ting Li 2,  Qiu-Yin Wang 2,  Xu Zhang 2,  Yi-Meng Zheng 2,  Yan-Qing Wen 3,  Fan-Hao Meng 4,  Ting-Jian Zhang 5
Affiliations

Affiliations

  • 1 School of Pharmacy / Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs, China Medical University, 77 Puhe Road, North New Area, Shenyang, 110122, China; School of Pharmacy, Anhui Xinhua University, 555 Wangjiangxi Road, High-tech Zone, Hefei, 230088, China.
  • 2 School of Pharmacy / Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs, China Medical University, 77 Puhe Road, North New Area, Shenyang, 110122, China.
  • 3 School of Pharmacy / Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs, China Medical University, 77 Puhe Road, North New Area, Shenyang, 110122, China; Department of Pharmacy, The Fourth Affiliated Hospital of China Medical University, Shenyang, China. Electronic address: yqwen@cmu.edu.cn.
  • 4 School of Pharmacy / Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs, China Medical University, 77 Puhe Road, North New Area, Shenyang, 110122, China. Electronic address: fhmeng@cmu.edu.cn.
  • 5 School of Pharmacy / Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs, China Medical University, 77 Puhe Road, North New Area, Shenyang, 110122, China. Electronic address: tjzhang@cmu.edu.cn.
PMID: 40570414 DOI: 10.1016/j.ejmech.2025.117895
Abstract

A series of 2-benzyl-4-substituted-2-azabicyclo[3.2.1]octanes, derived from the E-F ring of aconitine scaffold, were designed as potential Anticancer agents. Utilizing two key reactions, asymmetric aza-Diels-Alder addition and SN2 type ring expansion, to construct the core bicyclic skeleton, forty-one target compounds (11a-v and 13a-s) were successfully synthesized. Most of the target compounds exhibited considerable antiproliferative effects against four Cancer cell lines (A549, HT-29, HepG2 and MDA-MB 231) with low IC50 values. Among them, compound 13l showed the most potent antiproliferative activity against HT-29 colorectal Cancer (CRC) cells, and displayed significant heat shock protein 90 (HSP90) inhibitory activity. Molecular modeling studies supported the experimental results and the key interactions were identified. Further investigation indicated that 13l could effectively suppress the proliferation and migration of HT-29 cells, along with inducing cell cycle arrest and mild Apoptosis via down-regulation of CDK12, CDK13 and Bcl-2 protein expressions, and up-regulation of Bax. Mechanistic studies revealed that 13l could inhibit HSP90 to destabilize EGFR and suppress the activation of the EGFR-Akt signaling pathway to reduce proliferation of HT-29 cells. Consistent with in vitro results, 13l significantly repressed tumor growth in an HT-29 xenograft mouse model without causing evident cytotoxicity. Therefore, 13l could be considered as a novel and potentially effective candidate for the future treatment of CRC.

Keywords

Aconitine; Antiproliferative activity; Colorectal cancer; Hsp90 inhibitors; Structural optimization.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-176279
    Hsp90抑制剂
    HSP
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