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Exploring zingerone 2-thiohydantoins as anticancer agents against breast adenocarcinoma: Cytotoxicity, HSA and DNA
Petar Stanić1, Ana Rilak-Simović1, Katarina Virijević1
1Institute for Information Technologies, University of Kragujevac, Serbia.
Abstract:
This study investigates a series of zingerone 2-thiohydantoins for anticancer activity towards human breast adenocarcinoma and explores possible mechanisms of anticancer action. Cytotoxicity was tested on highly invasive triple negative breast cancer MDA-MB-231 cells and healthy MRC-5 cells. The most active compound 2e exerted a significant cytotoxic effect on breast cancer cells, while exhibiting no measurable toxicity on healthy cells. Fluorescence measurements of interactions with human serum albumin, combined with molecular docking, showed strong binding and transport capabilities, suggesting good bioavailability. Fluorescence and hydrodynamic measurements with DNA displayed lower binding affinity, suggesting that protein targets are responsible for anticancer action. Thorough molecular docking screening on 36 possible breast adenocarcinoma protein targets was performed and results suggest competitive inhibition of DNA methyltrasferase 1 as the mechanism of anticancer action. ADMET analysis predicted favorable physicochemical and pharmacokinetic properties.
Insights
This study explored zingerone 2-thiohydantoins for anticancer activity against human breast cancer. Compound 2e showed significant cancer cell cytotoxicity with no toxicity to healthy cells, suggesting potential therapeutic applications.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cancer Biology
Background:
- Breast adenocarcinoma is a significant global health concern.
- Triple-negative breast cancer (TNBC) presents a therapeutic challenge due to its aggressiveness.
- Zingerone derivatives are being investigated for novel therapeutic properties.
Purpose of the Study:
- To synthesize and evaluate zingerone 2-thiohydantoins for anticancer activity against human breast cancer cells.
- To elucidate the mechanism of action for the most potent compounds.
- To assess the pharmacokinetic and safety profiles of promising candidates.
Main Methods:
- Synthesis of zingerone 2-thiohydantoins.
- In vitro cytotoxicity assays using MDA-MB-231 (TNBC) and MRC-5 (healthy) cell lines.
- Fluorescence spectroscopy and molecular docking to study protein and DNA interactions.
- ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis.
Main Results:
- Compound 2e demonstrated significant selective cytotoxicity against MDA-MB-231 cells, with no observed toxicity in MRC-5 cells.
- Fluorescence and docking studies indicated strong binding to human serum albumin, suggesting good bioavailability.
- Lower binding affinity to DNA suggested protein targets are key for anticancer action.
- Molecular docking identified DNA methyltransferase 1 (DNMT1) as a potential target, with compound 2e acting as a competitive inhibitor.
- Predicted favorable ADMET properties for compound 2e.
Conclusions:
- Zingerone 2-thiohydantoin derivative 2e exhibits potent and selective anticancer activity against triple-negative breast cancer.
- The anticancer mechanism likely involves the competitive inhibition of DNA methyltransferase 1.
- Compound 2e possesses favorable properties for further drug development as a breast cancer therapeutic.
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