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Updated: Jan 13, 2026
Author Spotlight: Characterizing DNA G-Quadruplex by Bis-3-Chloropiperidine Based Chemical Mapping
Published on: May 12, 2023
Exploration of chromenone-based ligands as DNA G-quadruplex targets in triple-negative breast cancer
Phooi Yan Mock1, Eng Wee Chua1, Aaron Stevens2
1Centre for Drug and Herbal Development, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
Abstract:
Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic subtype of breast cancer with limited treatment options and poor prognosis. Therefore, there is a pressing need for novel anti-cancer treatments for TNBC. G-quadruplexes (G4s), secondary nucleic acid structures, play essential biological roles in regulating the expression of oncogenes. With the discovery of G4 structures in oncogenes related to breast cancer, G4 ligands have gained interest as promising candidates for TNBC treatment. This study aimed to investigate the potential of chromenone derivatives as G4 ligands with novel pharmacophores and to evaluate their in vitro anti-TNBC activity. In this study, three series of chromenone derivatives with various amine substitutions at different positions were synthesized and tested against TNBC cells. Among them, compound 17, bearing two N-methyl piperazine moieties, exhibited notable cytotoxicity towards TNBC cell lines. Mechanistic investigation revealed that it downregulated hTERT expression, thereby likely exerting an anti-cancer effect by binding and stabilizing the hTERT G4, with high selectivity and affinity for parallel G4 structures. In line with this, compound 17 was found to inhibit the non-canonical functions of hTERT, leading to S/G2 cell cycle arrest and apoptosis. This study offers insights into the potential application of chromenone as a novel pharmacophore for G4-stabilizing ligands in the development of anti-TNBC therapeutics.
Insights
Chromenone derivatives show promise as novel treatments for triple-negative breast cancer (TNBC). Compound 17 effectively targeted cancer cells by stabilizing G-quadruplex structures in the hTERT oncogene, leading to cell death.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) is aggressive with limited therapeutic options.
- G-quadruplexes (G4s) are key regulators of oncogene expression and potential therapeutic targets.
- G4 ligands are emerging as promising anti-cancer agents for TNBC.
Purpose of the Study:
- To synthesize and evaluate novel chromenone derivatives as G-quadruplex (G4) ligands.
- To assess the in vitro anti-TNBC activity of these compounds.
- To investigate the mechanism of action for promising candidates.
Main Methods:
- Synthesis of three series of chromenone derivatives with diverse amine substitutions.
- In vitro cytotoxicity assays against TNBC cell lines.
- Mechanistic studies including hTERT expression analysis, G4 binding affinity, cell cycle analysis, and apoptosis assays.
Main Results:
- Compound 17, featuring N-methyl piperazine moieties, demonstrated significant cytotoxicity against TNBC cells.
- Compound 17 downregulated hTERT expression, indicating binding and stabilization of the hTERT G4 structure.
- The compound selectively targeted parallel G4 structures, induced S/G2 cell cycle arrest, and promoted apoptosis.
Conclusions:
- Chromenone derivatives can serve as effective G4-stabilizing ligands.
- Compound 17 exhibits potential as a novel therapeutic agent for TNBC.
- This study highlights chromenone as a promising pharmacophore for developing new anti-TNBC drugs targeting G4 structures.
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