Copper complexes with quinoline-thiosemicarbazone hybrid ligand promoting apoptosis by causing DNA and mitochondria dual lesions

• Published in: Journal of molecular structure 2024-10, Vol.1314, p.138719, Article 138719
• Main Authors: Hu, Jiyong, Guo, Yan, Mao, Ruina, Dang, Liyun, Gu, Zhenzhen, Wang, Zhe, Ji, Feixiang, Zhao, Jin'an
• Format: Article
• Language: English
• Subjects: Antitumor; Copper complex; Mitochondrial dysfunction; ROS; Thiosemicarbazone
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2024.138719

•Two thiosemicarbazone-based Cu complexes with proapoptotic activity were synthesized.•Complex 1 bound to DNA via an intercalation mode and arrested cell cycle in S phase.•Complex 1 enhanced ROS generation, caused mitochondria dysfunction and ATP depletion. The copper ion and thiosemicarbazone group are well known for their biological activity, endowing the thiosemicarbazone copper complexes with medicinal perspectives. In this work, two copper complexes [Cu(qcpt)(PPh3)2Br]·2CH3CN (1) and [Cu2(qcapt)(Ac)2(CH3O)] (2) derived from the bioactive quinoline-thiosemicarbazone conjugate (qcpt = quinoline-2- carboxaldehyde-4-pyridine-3-thiosemicarbazone; qcapt = quinoline-2-carboxaldehyde acid-4- pyridine-3-thiosemicarbazone) were rationally synthesized and characterized by single crystal X-ray diffraction, Infrared (IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and etc. In vitro antitumor studies suggested that complexes 1 and 2 showed effective anti-proliferative activity against malignant tumor cells, especially for complex 1 that exhibited the most sensitive against SMMC7721 cells (human liver carcinoma cell lines). Further, mechanistic studies showed that complex 1 could readily enter the cells, block the cell cycle, cause mitochondrial dysfunction and ATP depletion, enhance the levels of intracellular reactive oxygen species (ROS), and eventually trigger cell death via apoptosis. Additionally, complex 1 bound to CT-DNA via an intercalation mode as evidenced by spectroscopic experiments, molecular docking study and cleaved pBR322 DNA efficiently in the presence of H2O2. Copper complex 1 demonstrated most sensitive against SMMC7721 cells. The mechanistic studies elucidated that complex 1 could enter the cells, arrest the cell cycle, elicit ROS overproduction and cause mitochondrial dysfunction accompanied with ATP depletion. Eventually, complex 1 triggered apoptotic tumor cell death. [Display omitted]