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

Jelena D Dimitrijević; Natalija Solovjova; Andriana M Bukonjić; Dušan Lj Tomović; Mirjana Milinkovic; Angelina Caković; Jovana Bogojeski; Zoran R Ratković; Goran V Janjić; Aleksandra A Rakić; Nebojsa N Arsenijevic; Marija Z Milovanovic; Jelena Z Milovanovic; Gordana P Radić; Verica V Jevtić

doi:10.3390/ijms241512504

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

Int J Mol Sci. 2023 Aug 6;24(15):12504. doi: 10.3390/ijms241512504.

Authors

Jelena D Dimitrijević¹, Natalija Solovjova², Andriana M Bukonjić³, Dušan Lj Tomović³, Mirjana Milinkovic¹, Angelina Caković⁴, Jovana Bogojeski⁴, Zoran R Ratković⁴, Goran V Janjić⁵, Aleksandra A Rakić⁶, Nebojsa N Arsenijevic^{7

8}, Marija Z Milovanovic^{1

7}, Jelena Z Milovanovic^{1

9}, Gordana P Radić³, Verica V Jevtić⁴

Affiliations

¹ Center for Harm Reduction of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, Serbia, Svetozara Markovića 69, 34000 Kragujevac, Serbia.
² Academy of Applied Studies Belgrade, The College of Health Science, Cara Dušana 254, 11080 Belgrade, Serbia.
³ Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia.
⁴ Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovic 12, 34000 Kragujevac, Serbia.
⁵ National Institute of the Republic of Serbia, Department of Chemistry, Technology and Metallurgy, University of Belgrade-Institute of Chemistry, Njegoševa 12, 11000 Belgrade, Serbia.
⁶ Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12-16, 11158 Belgrade, Serbia.
⁷ Faculty of Medical Sciences, Department of Microbiology and Immunology, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia.
⁸ Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia.
⁹ Faculty of Medical Sciences, Department of Histology and Embryology, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia.

Abstract

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.

Keywords: CT26 cells; DNA interaction; antitumor activity; binuclear copper(II) complexes; colon cancer; cytotoxicity; docking studies; inflammation.

Grants and funding

The authors gratefully acknowledge the financial support from the Ministry of Science, Technological Development and Innovation of the Republic of Serbia (No. 451-03-47/2023-01/200122, 451-03-47/2023-01/200026, 451-03-47/2023-01/200146, and 451-03-47/2023-01/200111), Science Fund of the Republic of Serbia (the Serbian Science and Diaspora Collaboration Program: Project acronym: TransMeCo), and The Faculty of Medical Sciences, University of Kragujevac (MP 02/19, JP 18/19, JP 19/19).