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Synthesis, anticancer activity, and β-lactoglobulin binding interactions of multitargeted kinase inhibitor sorafenib
Hamid Tanzadehpanah1, Asrin Bahmani1, Neda Hosseinpour Moghadam1
1Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
Abstract:
Sorafenib tosylate (SORt) is an oral multikinase inhibitor used for treatment of advanced renal cell, liver, and thyroid cancers. In this study, this drug was synthesized and its antiproliferative activities against HCT116 and CT26 cells were assessed. The interaction of SORt with β-lactoglobulin (BLG) was studied using different fluorescence techniques, circular dichroism (CD), zeta potential measurements, and docking simulation. The results of infrared (IR), mass, H NMR, and C NMR spectra demonstrated that the drug was produced with high quality, purity, and efficiency. SORt showed potent cytotoxicity against HCT116 and CT26 cells with IC50 of 8.12 and 5.42 μM, respectively. For BLG binding of SORt, the results showed that static quenching was the cause of the high affinity drug-protein interaction. Three-dimensional fluorescence and synchronous spectra indicated that SORt conformation was changed at different levels. CD suggested that the α-helix content remained almost constant in the BLG-SORt complex, whereas random coil content decreased. Zeta potential values of BLG were more positive after binding with SORt, due to electrostatic interactions between BLG and SORt. Thermodynamic parameters confirmed van der Waals and hydrogen bond interactions in the complex formation. Molecular modelling predicted the presence of hydrogen bonds and electrostatic forces in the BLG-SORt system, which was consistent with the experimental results.
Insights
This study synthesized sorafenib tosylate (SORt), confirming its high purity and potent anticancer activity. Researchers also detailed SORt
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Sorafenib tosylate (SORt) is a crucial oral multikinase inhibitor for advanced cancers.
- Understanding drug-protein interactions is vital for optimizing therapeutic efficacy.
Purpose of the Study:
- To synthesize and characterize SORt.
- To evaluate the antiproliferative effects of SORt on cancer cell lines.
- To investigate the molecular interactions between SORt and beta-lactoglobulin (BLG).
Main Methods:
- Synthesis and spectroscopic characterization (IR, Mass, NMR) of SORt.
- In vitro cytotoxicity assays (IC50 determination) against HCT116 and CT26 cells.
- Biophysical techniques (fluorescence, CD, zeta potential) and molecular docking to study SORt-BLG interaction.
Main Results:
- High-quality SORt was synthesized, exhibiting potent cytotoxicity (IC50: 8.12 μM for HCT116, 5.42 μM for CT26).
- SORt binds to BLG via static quenching, indicating a high-affinity interaction.
- SORt binding induced conformational changes in BLG, with electrostatic and hydrogen bonding interactions confirmed by biophysical and computational methods.
Conclusions:
- The synthesized SORt is a high-purity, effective anticancer agent.
- SORt interacts with BLG through a combination of forces, including hydrogen bonds and electrostatic interactions.
- These findings provide insights into the drug-protein binding mechanisms of SORt.
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