Synthesis of naphthalimide-carborane and metallacarborane conjugates: Anticancer activity, DNA binding ability
| Autor: | Rafał A. Bachorz, Agnieszka Fedoruk-Wyszomirska, Agnieszka Kiliszek, Marta Orlicka-Płocka, Eliza Wyszko, Małgorzata Giel-Pietraszuk, Agnieszka B. Olejniczak, Sebastian Rykowski, Dorota Gurda, Bohumír Grüner, Daria Różycka, Wojciech Rypniewski, Jan Nekvinda, Jakub Wojcieszak |
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| Rok vydání: | 2019 |
| Předmět: |
Mitochondrial ROS
Programmed cell death Cell cycle checkpoint Antineoplastic Agents 01 natural sciences Biochemistry Cell Line chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Organometallic Compounds Humans Cytotoxicity Boranes Molecular Biology Cell Proliferation Binding Sites Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry DNA Neoplasm Hep G2 Cells Cell cycle 0104 chemical sciences 010404 medicinal & biomolecular chemistry Naphthalimides Oxidative Stress Apoptosis Carborane Drug Screening Assays Antitumor DNA |
| Zdroj: | Bioorganic chemistry. 94 |
| ISSN: | 1090-2120 |
| Popis: | The development of 1,8-naphthalimide derivatives as DNA-targeting anticancer agents is a rapidly growing area and has resulted in several derivatives entering into clinical trials. One of original recent developments is the use of boron clusters: carboranes and metallacarboranes in the design of pharmacologically active molecules. In this direction several naphthalimide-carborane and metallacarborane conjugates were synthesized in the present study. Their effect on a cancer cell line – cytotoxicity, type of cell death, cell cycle, and ROS production were investigated. The tested conjugates revealed different activities than the leading members of the naphthalimides family, namely mitonafide and pinafide. These derivatives could induce G0/G1 arrest and promote mainly apoptosis in HepG2 cell line. Our investigations demonstrated that the most promising molecule is N-{[2-(3,3′-commo-bis(1,2-dicarba-3-cobalta(III)-closo-dodecaborate-1-yl)ethyl]-1′-aminoethyl)}-1,8-naphthalimide] (17). It was shown that 17 exhibited cytotoxicity against HepG2 cells, activated cell apoptosis, and caused cell cycle arrest in HepG2 cells. Further investigations in HepG2 cells revealed that compound 17 can also induce ROS generation, particularly mitochondrial ROS (mtROS), which was also proved by increased 8-oxo-dG level in DNA. Additionally to biological assays the interaction of the new compounds with ct-DNA was studied by CD spectra and melting temperature, thus demonstrating that these compounds were rather weak classical DNA intercalators. |
| Databáze: | OpenAIRE |
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