Structure-activity relationship and cytotoxicity of the new thiosemicarbazide derivatives and their Cu(II) complexes against prostate and melanoma cancer cells

Bartłomiej Rogalewicz; Monika Pitucha; Marcin Świątkowski; Ewelina Humeniuk; Grzegorz Adamczuk; Monika Drózd; Zbigniew Karczmarzyk; Elżbieta Kuśmierek; Krzysztof Strzelec; Anita Raducka; Waldemar Wysocki; Alina Olender; Anna Kozub; Dorota Kowalczuk; Ewa Poleszak; Agnieszka Czylkowska

doi:10.1016/j.abb.2024.109955

Structure-activity relationship and cytotoxicity of the new thiosemicarbazide derivatives and their Cu(II) complexes against prostate and melanoma cancer cells

Arch Biochem Biophys. 2024 May:755:109955. doi: 10.1016/j.abb.2024.109955. Epub 2024 Mar 7.

Authors

Bartłomiej Rogalewicz¹, Monika Pitucha², Marcin Świątkowski³, Ewelina Humeniuk⁴, Grzegorz Adamczuk⁴, Monika Drózd², Zbigniew Karczmarzyk⁵, Elżbieta Kuśmierek³, Krzysztof Strzelec⁶, Anita Raducka³, Waldemar Wysocki⁵, Alina Olender⁷, Anna Kozub⁸, Dorota Kowalczuk⁹, Ewa Poleszak¹⁰, Agnieszka Czylkowska¹¹

Affiliations

¹ Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924, Lodz, Poland. Electronic address: bartlomiej.rogalewicz@dokt.p.lodz.pl.
² Independent Radiopharmacy Unit, Faculty of Pharmacy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland.
³ Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924, Lodz, Poland.
⁴ Independent Medical Biology Unit, Faculty of Pharmacy, Medical University of Lublin, Jaczewskiego 8b, 20-093, Lublin, Poland.
⁵ Department of Chemistry, University of Siedlce, 3 Maja 54, 08-110, Siedlce, Poland.
⁶ Institute of Polymer & Dye Technology, Faculty of Chemistry, Lodz University of Technology, Stefanowskiego 12/16, 90-924, Lodz, Poland.
⁷ Chair and Department of Medical Microbiology, Medical University of Lublin, Chodzki 1, 20-093, Lublin, Poland.
⁸ Department of Bioanalytics, Faculty of Biomedicine, Medical University of Lublin, Jaczewskiego 8b, 20-090, Lublin, Poland.
⁹ Chair and Department of Medicinal Chemistry, Faculty of Pharmacy, Medical University of Lublin, Jaczewskiego 4, 20-090, Lublin, Poland.
¹⁰ Laboratory of Preclinical Testing, Chair and Department of Applied and Social Pharmacy, Medical University of Lublin, Chodzki 1, 20-093, Lublin, Poland.
¹¹ Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924, Lodz, Poland. Electronic address: agnieszka.czylkowska@p.lodz.pl.

PMID: 38460659
DOI: 10.1016/j.abb.2024.109955

Abstract

In this study, eighteen new ligands (B1-B18) containing a thiosemicarbazide core were synthesized and characterized in terms of physicochemical properties, molecular docking and in vitro biological activity. The structures of eleven ligands were investigated using X-Ray diffraction and Hirschfeld Surface analysis. To study the structure-activity relationship, the organic ligands contained pyridin-2-ylmethyl, pyridin-3-ylmethyl or pyridin-4-ylmethyl moieties and various substituents. Their pharmakokinetic profiles and molecular docking results suggest high potential as new drug candidates. The complexing ability of the selected organic ligands was also evaluated, yielding five new Cu(II) complexes (Cu(B1)Cl₂, Cu(B4)Cl₂, Cu(B10)Cl₂, Cu(B17)Cl₂, Cu(B18)Cl₂). The obtained results suggest the formation of the polymeric structures. All organic ligands and Cu(II) complexes were tested for anticancer activity against prostate and melanoma cancer cells (PC-3, DU-145, LNCaP, A375, G-361, SK-MEL-28) and normal fibroblasts (BJ), as well as antimicrobial activity against six selected bateria strains. Among B1-B18 compounds, B3, B5, B9, B10, B12 and B14 exhibited cytotoxic activity. The studied Cu(II) complexes were in general more active, with Cu(B1)Cl₂ exhibiting antincancer activity agains all three prostate cancer cells and Cu(B10)Cl₂ reaching the IC₅₀ value equal to 88 μM against G-361 melanoma cells. Several compounds also exhibited antimicrobial activity against gram-positive and gram-negative bacteria. It was found that the type of specific substituents, especially the presence of -chloro and -dichloro substituents had a greated impact on the cytotoxicity than the position of the nitrogen atom in the pyridylacetyl moiety.

Keywords: Antimicrobial and anticancer activity; Cu(II) complex; FTIR spectroscopy; Thiosemicarbazide derivative; X-ray analysis.