Ruthenium(II)-Dithiocarbazates as Anticancer Agents: Synthesis, Solution Behavior, and Mitochondria-Targeted Apoptotic Cell Death

Abstract

The reaction of the Ru(PPh₃ )₃ Cl₂ with HL^1-3 -OH (-OH stands for the oxime hydroxyl group; HL¹ -OH=diacetylmonoxime-S-benzyldithiocarbazonate; HL² -OH=diacetylmonoxime-S-(4-methyl)benzyldithiocarbazonate; and HL³ -OH=diacetylmonoxime-S-(4-chloro)benzyl-dithiocarbazonate) gives three new ruthenium complexes [Ru^II (L^1-3 -H)(PPh₃ )₂ Cl] (1-3) (-H stands for imine hydrogen) coordinated with dithiocarbazate imine as the final products. All ruthenium(II) complexes (1-3) have been characterized by elemental (CHNS) analyses, IR, UV-vis, NMR (¹ H, ¹³ C, and ³¹ P) spectroscopy, HR-ESI-MS spectrometry and also, the structure of 1-2 was further confirmed by single crystal X-ray crystallography. The solution/aqueous stability, hydrophobicity, DNA interactions, and cell viability studies of 1-3 against HeLa, HT-29, and NIH-3T3 cell lines were performed. Cell viability results suggested 3 being the most cytotoxic of the series with IC₅₀ 6.9±0.2 μM against HeLa cells. Further, an apoptotic mechanism of cell death was confirmed by cell cycle analysis and Annexin V-FITC/PI double staining techniques. In this regard, the live cell confocal microscopy results revealed that compounds primarily target the mitochondria against HeLa, and HT-29 cell lines. Moreover, these ruthenium complexes elevate the ROS level by inducing mitochondria targeting apoptotic cell death.

Keywords: DNA interaction; cytotoxicity; mitochondria-mediated apoptosis; ruthenium(II)-dithiocarbazates; solution study.