Metal NHC Complexes with Naphthalimide Ligands as DNA-Interacting Antiproliferative Agents

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RESEARCH PRODUCT

Metal NHC Complexes with Naphthalimide Ligands as DNA-Interacting Antiproliferative Agents

Ingo Ott Rainer Misgeld Alessio Terenzi Alessio Terenzi Peter G. Jones Wojciech Streciwilk Aram Prokop Corazon Frias Bernhard K. Keppler Bernhard K. Keppler

subject

Circular dichroism Stereochemistry Intercalation (chemistry)Molecular Conformation chemistry.chemical_element Apoptosis Crystallography X-Ray Ligands 010402 general chemistry 01 natural sciences Biochemistry Rhodium Metal chemistry.chemical_compound Drug Stability Coordination Complexes Drug Discovery Humans Moiety General Pharmacology Toxicology and Pharmaceutics ruthenium Cell Proliferation Pharmacology 010405 organic chemistry Chemistry Circular Dichroism Organic Chemistry DNA naphthalimide Intercalating Agents anticancer agent 0104 chemical sciences Ruthenium carbene Naphthalimides Settore CHIM/03 - Chimica Generale E Inorganica copper visual_art rhodium MCF-7 Cells Monoterpenes visual_art.visual_art_medium Cymenes Molecular Medicine Spectrophotometry Ultraviolet HT29 Cells Methane Carbene DNA

description

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.

year	journal	country	edition	language
2017-01-23	ChemMedChem

https://doi.org/10.1002/cmdc.201600557