title: Metal NHC Complexes with Naphthalimide Ligands as DNA-Interacting Antiproliferative Agents.
abstract: Naphthalimide-based N-heterocyclic carbene (NHC) complexes of the type [(1,5-cyclooctadiene)(NHC)RhCl)] (4 a-c), [(p-cymene)(NHC)RuCl2)] (5 a-c), and [(NHC)CuBr] (6 a-c) were synthesized and investigated as antiproliferative agents that target DNA. The cytotoxic effects were largely driven by the naphthalimide structure, which is a DNA-intercalating moiety. Regarding the metal center, the highest activities were observed with the rhodium complexes, and cytotoxic activity was significantly lower for the ruthenium derivatives. The stable coordination of the NHC ligands of selected complexes 4 b and 5 b in solution was confirmed, and their DNA binding properties were studied by UV/Vis spectroscopy, mass spectrometry, and circular dichroism. Stable intercalative binding into the DNA for all selected naphthalimide-based complexes is indicated by high DNA binding constants. Particularly efficient binding was observed in the case of the rhodium complex 4 b. More detailed biological studies on 4 b showed promising activities against multidrug-resistant Nalm-6 cells and confirmed an important role for mitochondrial pathways in 4 b-induced apoptosis.
authors.affiliation: Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstr. 55, 38106, Braunschweig, Germany.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Streciwilk
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Straße 42, 1090, Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Vienna, Austria.
authors.forename: Alessio
authors.initials: A
authors.lastname: Terenzi
authors.affiliation: Department of Paedriatric Oncology, Childrens Hospital Cologne, Amsterdamer Strasse 59, 50735, Cologne, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Misgeld
authors.affiliation: Department of Paedriatric Oncology, Childrens Hospital Cologne, Amsterdamer Strasse 59, 50735, Cologne, Germany.
authors.forename: Corazon
authors.initials: C
authors.lastname: Frias
authors.affiliation: Institute of Inorganic and Analytical Chemistry, Technische Universität Braunschweig, Postfach 3329, 38023, Braunschweig, Germany.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Jones
authors.affiliation: Department of Paedriatric Oncology, Childrens Hospital Cologne, Amsterdamer Strasse 59, 50735, Cologne, Germany.
authors.forename: Aram
authors.initials: A
authors.lastname: Prokop
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Straße 42, 1090, Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Vienna, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.affiliation: Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstr. 55, 38106, Braunschweig, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D018360:Crystallography, X-Ray; D000081007:Cymenes; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004355:Drug Stability; D019073:HT29 Cells; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D008024:Ligands; D061986:MCF-7 Cells; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D008968:Molecular Conformation; D039821:Monoterpenes / Q000737:chemistry; D053644:Naphthalimides / Q000737:chemistry*; D012238:Rhodium / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet
chemical_list: D056831:Coordination Complexes; D000081007:Cymenes; D007364:Intercalating Agents; D008024:Ligands; D039821:Monoterpenes; D053644:Naphthalimides; C007210:4-cymene; C030011:carbene; D012428:Ruthenium; D004247:DNA; D012238:Rhodium; D008697:Methane
keywords: anticancer agents; carbenes; copper; naphthalimides; rhodium; ruthenium