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 Bioorganic Chemistry Polish Academy of Sciences 12 14 Z Noskowskiego St 61 704 Poznan Poland

Institute of Inorganic Chemistry Academy of Sciences of the Czech Republic v v i Hlavní 1001 CZ 250 68 Řež Czech Republic

Institute of Inorganic Chemistry Academy of Sciences of the Czech Republic v v i Hlavní 1001 CZ 250 68 Řež Czech Republic; Department of Organic Chemistry Faculty of Sciences Charles University Hlavova 2030 128 42 Prague 2 Czech Republic

Institute of Medical Biology Polish Academy of Sciences 106 Lodowa St Lodz 93 232 Poland

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