Synthesis of naphthalimide-carborane and metallacarborane conjugates: Anticancer activity, DNA binding ability
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
31776032
DOI
10.1016/j.bioorg.2019.103432
PII: S0045-2068(19)31371-9
Knihovny.cz E-resources
- Keywords
- Anticancer activity, Carborane, Metallacarborane, Naphthalimides,
- MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Boranes chemistry pharmacology MeSH
- Cell Line MeSH
- Hep G2 Cells MeSH
- DNA, Neoplasm drug effects MeSH
- Drug Screening Assays, Antitumor MeSH
- Humans MeSH
- Molecular Structure MeSH
- Naphthalimides chemistry pharmacology MeSH
- Organometallic Compounds chemical synthesis chemistry pharmacology MeSH
- Oxidative Stress drug effects MeSH
- Cell Proliferation drug effects MeSH
- Binding Sites MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antineoplastic Agents MeSH
- Boranes MeSH
- DNA, Neoplasm MeSH
- Naphthalimides MeSH
- Organometallic Compounds MeSH
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.
Department of Pharmacodynamics Medical University of Lodz 1 Muszynskiego St 90 151 Lodz Poland
Institute of Medical Biology Polish Academy of Sciences 106 Lodowa St Lodz 93 232 Poland
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