Design, synthesis and evaluation of pterostilbene-indole hybrids as potential anticancer agents

  • Bioorg Med Chem Lett. 2025 Jun 26:128:130317. doi: 10.1016/j.bmcl.2025.130317.
Yingjie Xiao  1 ,  Jiawei Tang  1 ,  Shuoyu Zeng  1 ,  Zhaoxia Liu  1 ,  Lingyu Li  1 ,  Zhongmei Zou  2 ,  Hai Shang  3
Affiliations
  • 1. State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
  • 2. State Key Laboratory of Basis and New Drug Development of Natural and Nuclear Drugs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China. Electronic address: [email protected].
  • 3. State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China. Electronic address: [email protected].
PMID: 40581301 DOI: 10.1016/j.bmcl.2025.130317
Abstract

Pterostilbene is a natural product that exhibits Anticancer activity, primarily by targeting the JAK/STAT3 signaling pathway. To enhance the Anticancer efficacy of pterostilbene, a series of pterostilbene-indole hybrids were designed and synthesized via molecular hybridization with indole, aiming to develop novel STAT3 inhibitors, and preliminary structure-activity relationships (SAR) were established. Among them, 18q exhibited potent antitumor activity with IC50 values of 1.84 ± 0.41 μM (C6 cells) and 4.81 ± 1.12 μM (A549 cells). Flow cytometry analysis revealed its ability to promote late-stage Apoptosis. Additionally, 18q significantly suppressed tumor cell proliferation and migration, showing efficacy comparable to the positive control Vorinostat. It inhibited STAT3 phosphorylation, downregulated Bcl-2, and upregulated Caspase-3, indicating Apoptosis induction. The CETSA experiment showed that 18q could stabilize the thermal degradation of STAT3, proving that it was a direct inhibitor of STAT3. In conclusion, 18q is a promising STAT3 Inhibitor with robust antitumor activity.

Keywords
Anticancer; Mechanism of action; Pterostilbene-indole hybrids; STAT3 inhibitors.
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