Structural analysis and biological functionalities of iron(III)– and manganese(III)–thiosemicarbazone complexes: in vitro anti-proliferative activity on human cancer cells, DNA binding and cleavage studies

• Published in: Journal of biological inorganic chemistry 2019-05, Vol.24 (3), p.365-376
• Main Authors: Kaya, Büşra, Yılmaz, Zehra Kübra, Şahin, Onur, Aslim, Belma, Tükenmez, Ümmügülsüm, Ülküseven, Bahri
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry; Biomedical and Life Sciences; Calf thymus; Cattle; Cell Line, Tumor; Cervical carcinoma; Cervix; Colorectal carcinoma; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - drug effects; DNA Cleavage - drug effects; Electrostatic properties; Gel electrophoresis; Humans; Inorganic chemistry; Intercalating Agents - chemical synthesis; Intercalating Agents - chemistry; Intercalating Agents - pharmacology; Intercalation; Iron; Iron - chemistry; Life Sciences; Manganese; Manganese - chemistry; Microbiology; Molecular Structure; Original Paper; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology; Tumor cell lines
• ISSN: 0949-8257; 1432-1327
• DOI: 10.1007/s00775-019-01653-6

One iron(III) and two manganese(III) complexes based on thiosemicarbazone were synthesized and characterized using analytical and spectroscopic data. The crystallographic analysis showed the square pyramid structures of the complexes. Electronic spectra analysis was performed to determine the nature of the interaction between the complexes and calf thymus DNA (CT-DNA). DNA cleavage activities of the complexes were examined by gel electrophoresis (pBR322 DNA). The cytotoxicity of the complexes was determined against human cervical carcinoma (HeLa) and human colorectal adenocarcinoma (HT-29) cell lines by MTT assay. The results indicated that complex Fe1 is bound to CT-DNA via the intercalation mode, while complexes Mn1 and Mn2 are bound to CT-DNA via groove binding and/or electrostatic interactions rather than the intercalation mode. In addition, they showed good binding activity, which followed the order of Fe1 > Mn2 > Mn1. Complexes were found to promote the cleavage of DNA from supercoiled form (SC, Form I) to nicked circular form (NC, Form II) without concurrent formation of Form III, revealing the single-strand DNA cleavage. No significant cleavage was found in the presence of Mn1 and Mn2; however, it was observed at 2000 and 3000 µM concentrations of Fe1. The ability of Fe1 to cleave DNA was greater than that of other complexes and these results are in conformity with their DNA-binding affinities. Cytotoxicity determination tests revealed that the complex Fe1 on HeLa and HT-29 cells exhibited a higher anti-proliferative effect than Mn1 and Mn2 (Fe1 > Mn2 > Mn1). These studies suggested that the complex Fe1 could be a good candidate as a chemotherapeutic drug targeting DNA. Graphical abstract