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Published on: May 12, 2023
Design, synthesis, and mechanistic insights of quinoline-1(3H)-one derivatives as selective DNA intercalating agent
Utsab Debnath1, Satyajit Halder2, Chirantan Majumder3
1Department 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.
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.
Insights
Researchers developed a novel compound, 4l, showing high selectivity and potency against triple-negative breast cancer (TNBC). This DNA-binding agent offers a promising, less toxic therapeutic option for TNBC patients.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) is aggressive with limited treatment options.
- DNA-binding agents show anti-cancer potential but lack tumor selectivity and cause high toxicity.
- Developing selective therapies for TNBC is a critical unmet need.
Purpose of the Study:
- To design, synthesize, and optimize novel Quinoline-1(3H)-one derivatives targeting TNBC.
- To identify a potent and selective DNA-binding agent for TNBC treatment.
- To investigate the mechanism of action of the lead compound.
Main Methods:
- Rational design and synthesis of Quinoline-1(3H)-one derivatives.
- In vitro anticancer activity screening across multiple cancer cell lines.
- Cytotoxicity assessment in normal lung fibroblasts (WI-38).
- Comparative analysis with doxorubicin.
- In vitro studies on cell cycle, apoptosis, ROS generation, and mitochondrial membrane potential.
Main Results:
- Compound 4l demonstrated potent and selective activity against TNBC (IC50 = 2.08 ± 0.67 μM) with minimal toxicity to normal cells (CC50 ≥ 60 μM).
- Compound 4l exhibited a significantly higher selectivity index compared to doxorubicin.
- It induced G2/M cell cycle arrest and caspase-3 dependent apoptosis.
- The mechanism involves intracellular ROS generation, loss of mitochondrial membrane potential, and non-intercalative DNA binding.
Conclusions:
- Compound 4l is a highly promising candidate for selective TNBC therapy.
- Its non-intercalative DNA binding and targeted mechanism offer improved therapeutic potential.
- Further development of compound 4l could lead to a more effective treatment for triple-negative breast cancer.
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