Influence of Complexation of Thiosemicarbazone Derivatives with Cu (II) Ions on Their Antitumor Activity against Melanoma Cells.

Monika Pitucha,Agnieszka Czylkowska,Bartłomiej Rogalewicz,Monika Drozd,Magdalena Iwan,Agnieszka Korga-Plewko,Paulina Bartnik,Waldemar Wysocki,Zbigniew Karczmarzyk,Grzegorz Adamczuk,Ewelina Humeniuk,Emilia Fornal,Joanna Kubik

doi:10.3390/ijms22063104

Abstract

A series of thiosemicarbazone derivatives was prepared and their anti-tumor activity in vitro was tested. The X-ray investigation performed for compounds T2, T3 and T5 confirmed the synthesis pathway and assumed molecular structures of analyzed thiosemicarbazones. The conformational preferences of the thiosemicarbazone system were characterized using theoretical calculations by AM1 method. Selected compounds were converted into complexes of Cu (II) ions. The effect of complexing on anti-tumor activity has been investigated. The copper(II) complexes, with Schiff bases T1, T10, T12, T13, and T16 have been synthesized and characterized by chemical and elemental analysis, FTIR spectroscopy and TGA method. Thermal properties of coordination compounds were studied using TG-DTG techniques under dry air atmosphere. G361, A375, and SK-MEL-28 human melanoma cells and BJ human normal fibroblast cells were treated with tested compounds and their cytotoxicity was evaluated with MTT test. The compounds with the most promising anti-tumour activity were then selected and their cytotoxicity was verified with cell cycle analysis and apoptosis/necrosis detection. Additionally, DNA damages in the form of a basic sites presence and the expression of oxidative stress and DNA damage response genes were evaluated. The obtained results indicate that complexation of thiosemicarbazone derivatives with Cu (II) ions improves their antitumor activity against melanoma cells. The observed cytotoxic effect is associated with DNA damage and G2/M phase of cell cycle arrest as well as disorders of the antioxidant enzymes expression.

Highlights

Thiosemicarbazones are a group of sulfur derivatives of semicarbazones that are obtained as a result of the condensation of appropriate aldehydes or ketones and thiosemicarbazides in an acidic environment
The compound showed strong cardiotoxic properties, the search for safer analogues was started [10]. This led to the discovery of di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone, which was found to be effective in the treatment of neuroblastoma [11]
The newly obtained compounds were identified by modern spectroscopic methods

Summary

Introduction

Thiosemicarbazones are a group of sulfur derivatives of semicarbazones that are obtained as a result of the condensation of appropriate aldehydes or ketones and thiosemicarbazides in an acidic environment. The compound labeled Dp44mT (di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone) showed stronger antitumor effect than triapine and doxorubicin in in vitro studies, and was effective in the exposure of chemo- and radio-resistant cancer cell lines [8]. The potential of this molecule was to be used in the treatment of neuroblastoma, osteosarcoma and prostate cancer [9]. The compound showed strong cardiotoxic properties, the search for safer analogues was started [10] This led to the discovery of di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone, which was found to be effective in the treatment of neuroblastoma [11]. There have been reports on the biological activity of thiosemicarbazone derivative complexes [12,13,14,15]

Methods

Results

Conclusion