Docking Studies, Cytotoxicity Evaluation and Interactions of Binuclear Copper(II) Complexes with S-Isoalkyl Derivatives of Thiosalicylic Acid with Some Relevant Biomolecules

• Published in: International journal of molecular sciences 2023-08, Vol.24 (15), p.12504
• Main Authors: Dimitrijević, Jelena D, Solovjova, Natalija, Bukonjić, Andriana M, Tomović, Dušan Lj, Milinkovic, Mirjana, Caković, Angelina, Bogojeski, Jovana, Ratković, Zoran R, Janjić, Goran V, Rakić, Aleksandra A, Arsenijevic, Nebojsa N, Milovanovic, Marija Z, Milovanovic, Jelena Z, Radić, Gordana P, Jevtić, Verica V
• Format: Article
• Language: English
• Subjects: Acids; Amino acids; Analysis; Binding sites; Biochemistry; Biotechnology; Cancer; Cell cycle; Chemotherapy; Colon; Colon cancer; Colorectal cancer; Copper; Copper compounds; Cytotoxicity; Ligands; Sulfur; Viscosity
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241512504

The numerous side effects of platinum based chemotherapy has led to the design of new therapeutics with platinum replaced by another transition metal. Here, we investigated the interactions of previously reported copper(II) complexes containing S-isoalkyl derivatives, the salicylic acid with guanosine-5'-monophosphate and calf thymus DNA (CT-DNA) and their antitumor effects, in a colon carcinoma model. All three copper(II) complexes exhibited an affinity for binding to CT-DNA, but there was no indication of intercalation or the displacement of ethidium bromide. Molecular docking studies revealed a significant affinity of the complexes for binding to the minor groove of B-form DNA, which coincided with DNA elongation, and a higher affinity for binding to Z-form DNA, supporting the hypothesis that the complex binding to CT-DNA induces a local transition from B-form to Z-form DNA. These complexes show a moderate, but selective cytotoxic effect toward colon cancer cells in vitro. Binuclear complex of copper(II) with S-isoamyl derivative of thiosalicylic acid showed the highest cytotoxic effect, arrested tumor cells in the G2/M phase of the cell cycle, and significantly reduced the expression of inflammatory molecules pro-IL-1β, TNF-α, ICAM-1, and VCAM-1 in the tissue of primary heterotopic murine colon cancer, which was accompanied by a significantly reduced tumor growth and metastases in the lung and liver.