Ruthenium(II)-N-alkyl phenothiazine complexes as potential anticancer agents

Abstract

In recent years, the search for effective anticancer compounds based on transition metal complexes has been the focus of medical investigations. The synergy between the ruthenium(II) and N-alkylphenothiazine counter-ions (chlorpromazine hydrochloride, thioridazine hydrochloride and trifluoperazine dihydrochloride, respectively) through the formation of three different complexes (1-3) was investigated. We explored whether the selected counter-ions and complexes might affect redox homeostasis and genome integrity of normal human blood cells, and induce an inhibition of Na/K-ATPase and AChE at pharmacologically relevant doses. Our results have shown that counter-ions and complexes did not affect the activity of Na/K-ATPase, while AChE activity was inhibited in a dose-dependent manner. All investigated compounds disturbed the viability and redox homeostasis of lymphocytes. Complexes 1 and 2 displayed potent cytotoxic and prooxidant action while complex 3 behaved as a weaker genotoxic inducer. Still, the tested complexes appeared to be less genotoxic and more cytostatic than the corresponding counter-ions. The effects of selected complexes were also tested in PC12 and U2OS cancer cells with special attention being given to the ability of phenothiazines to affect dopamine D2 receptors. Using the confocal laser scanning microscopy, we observed that all the complexes reduced cell viability. Although all investigated complexes have been bound to the dopamine receptor D-eGFP, only complex 3 reduced its surface density and increased its lateral mobility in investigated cell lines. Albeit the role of alternative targets for complex 3 cannot be ruled out, its effects should be further examined as potential treatment strategy against cancer cells that overexpress D2.

Anticancer Potential of the S‐Heterocyclic Ring Containing Drugs and its Bioactivation to Reactive Metabolites

“…The complexes were able to bind to the dopamine receptors D2À eGFP and may act as potential against cancer cells overexpressing D2. [112]…”

“…The complexes were also tested against PC12 and U2OS cancer cells expressing D2 receptors. The complexes were able to bind to the dopamine receptors D2−eGFP and may act as potential against cancer cells overexpressing D2 [112] …”

Spectroscopic and electrochemical characterizations of copper complexes with thionine, azure C and azure A

“…Rigid cores in the transition metal complexes generally are formed by heterocyclic units with five-or six-membered rings containing nitrogen, oxygen or sulphur and carbon such as phenothiazine (PTZ) rings that is a complete example with their elements mentioned as shown in Figure 1. On the other hand, this type of rigid structure allows great potential for nonlinear optical materials, [1][2][3] optoelectronics and sensors, [3][4][5][6] photovoltaics, [7][8][9] energy storage, [10][11][12] catalysis, [13][14][15] medical imaging, [16][17][18] antimicrobial 19,20 and antiviral 21 activity and therapy [22][23][24] for academic and technological view.…”