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Triethylammonium salt of a synthesized dicoumarol: Structural insight and human anti-glioblastoma activities
Afzal Khan1,2,3, Muhammad Ikram1, Sadia Rehman1
1Department of Chemistry, Abdul Wali Khan University, Mardan, Pakistan.
Abstract:
Glioblastoma multiforme (GBM) is the most common and primary brain tumor with poor prognosis. They are removed by following tedious and life threatening surgeries. GBM stem cells (GSCs) are the main source of tumor recurrence after surgery. Hence, drugs are designed to overcome the recurrent glioblastoma malignant cells. Currently used chemotherapies are not cost effective as well as bear resistance. New and effective chemotherapeutic compounds are developed to overcome the intrinsic and acquired resistance. Dicoumarol derivative 3,3'-[(4-methoxyphenyl)methanediyl]bis(4-hydroxy-2Hchromen-2-one) (HL) and its triethylammonium salt triethylammonium3-[(4-methoxyphenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2-oxo-2H-chromen-4-olate (L) were synthesized and characterized using spectral and analytical techniques. The deprotonated compound L was further studied structurally using single crystal analysis. Cytotoxic studies against human glioblastoma cells A172 and LN229 were investigated both dose and time dependently and compared with the cytotoxicity of normal human astrocytes (NHA). The IC50 value of HL against A172 was found to be lying within the range 2.68-0.95 μM whereas against LN229 the range was found to be 9.55-0.85 μM. Similarly, the compound L revealed range of 1.9-0.271 μM against A172 and 1.2-0.27 μM against LN229. Cell cycle arrest was observed in GBM cells treated with L compared to the control group, which suggested that L may trigger apoptosis in GBM cells according to cytotoxicity and flow cytometry results. The antioxidant activity of synthesized compounds was also investigated using DPPH free radicals.
Insights
New dicoumarol derivatives show potent anti-cancer activity against glioblastoma stem cells. These compounds offer a promising avenue for developing novel glioblastoma multiforme (GBM) therapies, potentially overcoming drug resistance and improving patient outcomes.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with a high recurrence rate, often driven by glioblastoma stem cells (GSCs).
- Current chemotherapies for GBM are limited by cost-effectiveness and acquired drug resistance.
- Novel therapeutic strategies are crucial to overcome treatment challenges in GBM.
Purpose of the Study:
- To synthesize and characterize novel dicoumarol derivatives as potential anti-cancer agents.
- To evaluate the cytotoxic effects of these compounds against human glioblastoma cell lines.
- To investigate the mechanism of action, including cell cycle arrest and apoptosis induction.
Main Methods:
- Synthesis and spectral characterization of dicoumarol derivatives (HL and L).
- In vitro cytotoxicity assays against A172 and LN229 glioblastoma cells and normal human astrocytes (NHA).
- Flow cytometry analysis to assess cell cycle progression and apoptosis.
- DPPH assay to evaluate antioxidant activity.
Main Results:
- The synthesized compounds HL and L exhibited significant dose- and time-dependent cytotoxicity against glioblastoma cell lines.
- Compound L demonstrated potent activity with IC50 values in the low micromolar range against both A172 and LN229 cells.
- Treatment with compound L induced cell cycle arrest in GBM cells, suggesting a potential apoptotic mechanism.
- Both compounds displayed antioxidant activity.
Conclusions:
- The novel dicoumarol derivatives, HL and L, possess significant cytotoxic and anti-proliferative effects against glioblastoma cells.
- Compound L shows promise as a chemotherapeutic agent for glioblastoma, potentially by inducing apoptosis.
- Further research into these compounds could lead to more effective treatments for glioblastoma multiforme.
