Cationic dinitrosyl iron complexes with thiourea exhibit selective toxicity to brain tumor cells in vitro

Abstract

The cytotoxic activity of a series of dinitrosyl iron complexes (DNICs) with thioureas against cells of different origin has been studied in this work. The cytotoxicity of the studied DNICs proved to be substantially different depending on the structure of the complexes and cell line. Complexes with thiourea and 1,3-dimethylthiourea were found to induce notable cell death in different cell lines of both cancerous and non-cancerous origin, while the N-ethylthiourea-bearing complex induced cell death in cells derived from brain tumors. The studied DNICs effectively release NO while decomposing in solutions, as follows from the electrochemical analysis. It was found that the cytotoxic effects of the studied DNICs did not correlate with their NO-donating ability, hence suggesting that their cytotoxic activity is, in a big part, defined by the long-lived nitrosyl iron–sulfur intermediates formed during the decomposition of the complexes. The structures of the products formed upon hydrolytic decomposition of all studied DNICs have been studied by electrospray ionization mass spectrometry. Stable high-molecular cluster ions containing NO groups namely [Fe₄S₃(NO)₇]⁻ (Roussin's “black salt” anion), [Fe₄S₃(NO)⁵]⁻, [Fe₄S₄(NO)₄]⁻, [Fe₄S₃(NO)₄]⁻ and [Fe₄S₃(NO)₆]⁻ have been detected in the solution of the N-ethylthiourea-bearing complex. The mechanism of Roussin's “black salt” anion formation in a solution of DNIC with N′-ethylthiourea was studied using density functional theory. This moved us near understanding the reasons for the formation of biologically active intermediates upon the decomposition of the complex with N′-ethylthiourea, which are apparently responsible for the unique antiglioma activity of the complex.