2. Academic Validation
  3. Design, synthesis, and mechanistic insights of quinoline-1(3H)-one derivatives as selective DNA intercalating agent targeting triple-negative breast cancer

Design, synthesis, and mechanistic insights of quinoline-1(3H)-one derivatives as selective DNA intercalating agent targeting triple-negative breast cancer

  • Bioorg Chem. 2026 Feb:169:109398. doi: 10.1016/j.bioorg.2025.109398.
Utsab Debnath 1,  Satyajit Halder 2,  Chirantan Majumder 3,  S K Batin Rahaman 4,  Anirban Manna 3,  Pravat Kumar Parida 5,  Anup Kumar Misra 6,  Kuladip Jana 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, School of Health Sciences & Technology, UPES, Dehradun 248007, India; Department of Chemical Sciences, Bose Institute, EN, 80, Sector V, Salt Lake City, Kolkata 700091, India. Electronic address: utsab.debnath@gmail.com.
  • 2 Department of Biological Sciences (Formerly Division of Molecular Medicine), Bose Institute, EN, 80, Sector V, Salt Lake City, Kolkata 700091, India; Department of Physiology, Jhargram Raj College, Jhargram College Rd, Jhargram, West Bengal 721507, India.
  • 3 Department of Biological Sciences (Formerly Division of Molecular Medicine), Bose Institute, EN, 80, Sector V, Salt Lake City, Kolkata 700091, India.
  • 4 Department of Pharmaceutical Sciences, School of Health Sciences & Technology, UPES, Dehradun 248007, India.
  • 5 Department of Biological Sciences, Indian Institute of Science Education and Research Berhampur, Ganjam, Odisha 760003, India.
  • 6 Department of Chemical Sciences, Bose Institute, EN, 80, Sector V, Salt Lake City, Kolkata 700091, India.
  • 7 Department of Biological Sciences (Formerly Division of Molecular Medicine), Bose Institute, EN, 80, Sector V, Salt Lake City, Kolkata 700091, India. Electronic address: kuladip@jcbose.ac.in.
PMID: 41418597 DOI: 10.1016/j.bioorg.2025.109398
Abstract

Triple negative breast Cancer remains one of the most aggressive malignancies with limited targeted therapies and poor survival outcomes. Although DNA-intercalating agents, including natural products exhibit anti-cancer potential by disrupting various cellular processes that rely on DNA-protein interactions, their therapeutic application is limited by poor tumor selectivity and high cytotoxicity to normal cells. Here, through rational design, synthesis and optimization, we have developed a series of novel Quinoline-1(3H)-one derivatives aimed at enhancing selectivity towards TNBC. While several synthesized molecules demonstrated promising Anticancer activity across multiple Cancer cell lines, compound 4l emerged as the most potent and selective DNA-binding agent, exhibiting low IC50 values in TNBC (IC50 = 2.08 ± 0.67 μM) with minimal cytotoxicity to WI-38 (CC50 = ≥60 μM) a normal lung fibroblasts cell. Importantly, comparative analyses revealed substantially higher selectivity index of compound 4l than the clinical DNA-binding drug doxorubicin. Further in vitro, studies demonstrated that Compound 4l induced G2/M cell cycle arrest and robust, Caspase-3 dependent Apoptosis. This response was driven by marked intracellular and mitochondrial ROS generation, loss of mitochondrial membrane potential, and non-intercalative electrostatic DNA binding. Collectively, these results highlight compound 4l as a promising, selective Anticancer candidate with improved therapeutic potential for TNBC.

Keywords

Caspase dependent apoptosis; DNA-intercalating agents; In-silico studies; Quinoline-1(3H)-one analogues; Reactive oxygen species; Triple negative breast cancer.

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