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Synthesis of Sorafenib-Ruthenium Complexes, Investigation of Biological Activities and Applications in Drug Delivery

Belma Zengin Kurt¹, Dilek Öztürk Civelek², Elmas Begüm Çakmak³

¹Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Bezmialem Vakif University, 34093 Istanbul, Türkiye.

Journal of Medicinal Chemistry

|March 12, 2024

Abstract:

Sorafenib, a multiple kinase inhibitor, is widely used as a first-line treatment for hepatocellular carcinoma. However, there is a need for more effective alternatives when sorafenib proves insufficient. In this study, we aimed to design a structure that surpasses sorafenib's efficacy, leading us to synthesize sorafenib-ruthenium complexes for the first time and investigate their properties. Our results indicate that the sorafenib-ruthenium complexes exhibit superior epidermal growth factor receptor (EGFR) inhibition compared to sorafenib alone. Interestingly, among these complexes, Ru3S demonstrated high activity against various cancer cell lines including sorafenib-resistant HepG2 cells while exhibiting significantly lower cytotoxicity than sorafenib in healthy cell lines. Further evaluation of cell cycle, cell apoptosis, and antiangiogenic effects, molecular docking, and molecular dynamics studies revealed that Ru3S holds great potential as a drug candidate. Additionally, when free Ru3S was encapsulated into polymeric micelles M1, enhanced cytotoxicity on HepG2 cells was observed. Collectively, these findings position Ru3S as a promising candidate for EGFR inhibition and warrant further exploration for drug development purposes.

Insights

New sorafenib-ruthenium complexes, particularly Ru3S, show enhanced EGFR inhibition and potent anti-cancer activity against resistant cells with lower toxicity. Encapsulation in micelles further boosts efficacy, positioning Ru3S as a promising drug candidate.

Area of Science:

Medicinal Chemistry
Oncology
Materials Science

Background:

Sorafenib is a first-line treatment for hepatocellular carcinoma but has limitations.
There is a need for more effective hepatocellular carcinoma treatments.
Developing novel drug candidates with improved efficacy and safety profiles is crucial.

Purpose of the Study:

To synthesize and characterize novel sorafenib-ruthenium complexes.
To evaluate the efficacy of these complexes in inhibiting EGFR.
To investigate the potential of a specific complex, Ru3S, as a drug candidate.

Main Methods:

Synthesis of sorafenib-ruthenium complexes.
In vitro evaluation of EGFR inhibition and cytotoxicity against cancer and healthy cell lines.
Assessment of cell cycle, apoptosis, and antiangiogenic effects.
Molecular docking and molecular dynamics simulations.
Encapsulation of Ru3S into polymeric micelles (M1) and evaluation of cytotoxicity.

Main Results:

Sorafenib-ruthenium complexes demonstrated superior EGFR inhibition compared to sorafenib alone.
Ru3S showed high activity against various cancer cell lines, including sorafenib-resistant HepG2 cells.
Ru3S exhibited significantly lower cytotoxicity in healthy cell lines than sorafenib.
Ru3S showed potential in cell cycle, apoptosis, and antiangiogenic studies.
Encapsulation of Ru3S in M1 micelles enhanced its cytotoxicity against HepG2 cells.

Conclusions:

Ru3S is a potent EGFR inhibitor with promising anti-cancer activity and a favorable safety profile.
Ru3S holds significant potential as a drug candidate for hepatocellular carcinoma treatment.
Further research and development of Ru3S are warranted for therapeutic applications.

Read full analysis

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