2. Academic Validation
  3. Synthesis of trifluoromethyl-containing spiro-epoxyindole-pyrrolidines via a DABCO-catalyzed [3 + 2] cycloaddition and their antitumor activities

Synthesis of trifluoromethyl-containing spiro-epoxyindole-pyrrolidines via a DABCO-catalyzed [3 + 2] cycloaddition and their antitumor activities

  • Bioorg Chem. 2025 Dec 16:169:109395. doi: 10.1016/j.bioorg.2025.109395.
Yang Shi 1,  Liang-Liang Zheng 2,  You-Ping Tian 3,  Tao Wang 4,  Zhang-Chao Dong 4,  Li-Juan Liu 4,  Ying Zhou 5,  Xiong-Wei Liu 6,  Bo-Wen Pan 7
Affiliations

Affiliations

  • 1 College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China; State Key Laboratory of Natural and Biomimetic Drugs, Beijing 100191, China; Guizhou Key Laboratory of Modern Traditional Chinese Medicine Creation, Guiyang 550025, China.
  • 2 Qiandongnan Prefecture Food and Drug Inspection and Testing Center, Kaili 556011, China.
  • 3 College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China; Guizhou Key Laboratory of Modern Traditional Chinese Medicine Creation, Guiyang 550025, China. Electronic address: tianyouping034@gzy.edu.cn.
  • 4 College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China.
  • 5 College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China; Guizhou Key Laboratory of Modern Traditional Chinese Medicine Creation, Guiyang 550025, China. Electronic address: zhouying@gzy.edu.cn.
  • 6 College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China; Guizhou Key Laboratory of Modern Traditional Chinese Medicine Creation, Guiyang 550025, China. Electronic address: liuxiongwei058@gzy.edu.cn.
  • 7 College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China; Guizhou Key Laboratory of Modern Traditional Chinese Medicine Creation, Guiyang 550025, China. Electronic address: bwpan@gzy.edu.cn.
PMID: 41422722 DOI: 10.1016/j.bioorg.2025.109395
Abstract

We report a concise and general DABCO-catalyzed [3 + 2] cycloaddition that enables rapid assembly of a library of trifluoromethyl-containing spiroepoxyindole-pyrrolidine derivatives (3a-3x) under mild, operationally simple conditions, providing the target scaffolds in good to excellent yields (53-99 %, except 3e: 36 %) with high diastereoselectivity. Structural assignments were supported by multinuclear NMR, HRMS and single-crystal X-ray analysis (3a). A subset of the library was screened for antiproliferative activity in HeLa and K562 cells; compound 3p emerged as the most active hit (K562, IC50 = 7.02 ± 0.89 μM) with low toxicity to normal NCM460 cells. Integrative network pharmacology and molecular docking nominated STAT3, PIK3CA and JAK2 as putative targets of 3p, and detailed docking predicted favorable binding modes for both stereoisomers. Target prioritization for experimental follow-up focused on JAK2: cell-based assays showed a concentration-dependent decrease in phosphorylated JAK2 (p-JAK2) with no change in total JAK2, and surface plasmon resonance (SPR) experiments with JAK2 immobilized on a CM5 chip confirmed direct binding of 3p. Kinetic analysis (1,1 L fit) returned ka = 46.60 × 103 M-1·s-1, kd = 5.19 × 10-2 s-1 and KD = 1.11 × 10-6 M, indicating micromolar affinity and appreciable residence time consistent with functionally relevant engagement. Together, the synthetic chemistry, in silico target nomination and orthogonal target-engagement data identify 3p as a promising lead for further optimization and mechanistic study.

Keywords

Antitumor activities; Cycloaddition reaction; Molecular docking; Spiro-pyrrolidine compound.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-180766
    JAK抑制剂
    JAK
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