Synthesis of naphthalimide-carborane and metallacarborane conjugates: Anticancer activity, DNA binding ability

• Published in: Bioorganic chemistry Vol. 94; p. 103432
• Main Authors: Nekvinda, Jan, Różycka, Daria, Rykowski, Sebastian, Wyszko, Eliza, Fedoruk-Wyszomirska, Agnieszka, Gurda, Dorota, Orlicka-Płocka, Marta, Giel-Pietraszuk, Małgorzata, Kiliszek, Agnieszka, Rypniewski, Wojciech, Bachorz, Rafał, Wojcieszak, Jakub, Grüner, Bohumir, Olejniczak, Agnieszka B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2020
• Subjects: Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding Sites; Boranes - chemistry; Boranes - pharmacology; Carborane; Cell Line; Cell Proliferation - drug effects; DNA, Neoplasm - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Metallacarborane; Molecular Structure; Naphthalimides; Naphthalimides - chemistry; Naphthalimides - pharmacology; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Oxidative Stress - drug effects; Structure-Activity Relationship; Naphthalimides; Metallacarborane; Carborane; Anticancer activity
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103432

[Display omitted] •A series of naphthalimide-carborane/metallacarborane conjugates were synthesized.•First example of X-ray analysis of naphthalimide-carborane was established.•Naphthalimide with carborane more cytotoxic then those containing metallacarborane.•Compound 17 induced mitochondrial ROS generation in HepG2 cells. 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.