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

• Published in: Chemistry : a European journal 2023-03, Vol.29 (18), p.e202202694-n/a
• Main Authors: Sahu, Gurunath, Patra, Sushree Aradhana, Lima, Sudhir, Das, Sanchita, Görls, Helmar, Plass, Winfried, Dinda, Rupam
• Format: Article
• Language: English
• Subjects: Annexin V; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor agents; Apoptosis; Cell cycle; Cell death; Cell Line, Tumor; Cell lines; Cell viability; Chemistry; Confocal microscopy; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Crystallography; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA interaction; HeLa Cells; Humans; Hydrophobicity; Hydroxyl groups; Imines; Mitochondria; mitochondria-mediated apoptosis; Mortality; NMR; Nuclear magnetic resonance; Ruthenium; Ruthenium - chemistry; Ruthenium compounds; ruthenium(II)-dithiocarbazates; Single crystals; solution study; Spectrometry; Spectroscopy
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202202694

The reaction of the Ru(PPh3)3Cl2 with HL1−3−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 [RuII(L1−3−H)(PPh3)2Cl] (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 (1H, 13C, and 31P) 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. Synthesis, characterization, ruthenium‐assisted oxime to imine transformation, solution/aqueous phase stability, hydrophobicity, DNA interaction, and cytotoxicity studies (cellular localization, and apoptosis) of three new ruthenium(II)‐dithiocarbazate complexes are documented. This report reveals the detailed study of Ru(II) complexes as effective anticancer agents by inducing a mitochondrial‐targeted apoptotic mode of cell death in human cancer cells.