A Fluorescent Silver(I) Carbene Complex with Anticancer Properties: Synthesis, Characterization, and Biological Studies

• Published in: ChemMedChem Vol. 14; no. 1; pp. 182 - 188
• Main Authors: Fabbrini, Maria Giulia, Cirri, Damiano, Pratesi, Alessandro, Ciofi, Lorenzo, Marzo, Tiziano, Guerri, Annalisa, Nistri, Silvia, Dell'Accio, Alfonso, Gamberi, Tania, Severi, Mirko, Bencini, Andrea, Messori, Luigi
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 08.01.2019
• Subjects: anticancer drugs; Anticancer properties; Antitumor activity; Binding; Biological properties; Cancer; Cytotoxicity; fluorescence; Fluorescent indicators; Internalization; mass spectrometry; Neuroblastoma cells; Organic solvents; Physiological effects; Proteins; Reductase; Silver; silver carbene complexes; Silver chloride; Thioredoxin; thioredoxin reductase; mass spectrometry; fluorescence; anticancer drugs; silver carbene complexes; thioredoxin reductase
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201800672

The silver(I) N‐heterocyclic carbene (NHC) complex bis(1‐(anthracen‐9‐ylmethyl)‐3‐ethylimidazol‐2‐ylidene) silver chloride ([Ag(EIA)2]Cl), bearing two anthracenyl fluorescent probes, has been synthesized and characterized. [Ag(EIA)2]Cl is stable in organic solvents and under physiological conditions, and shows potent cytotoxic effects in vitro toward human SH‐SY5Y neuroblastoma cells. The interactions of [Ag(EIA)2]Cl with a few model biological targets have been studied as well as its ability to be internalized in cells. The in vitro anticancer activity is apparently related to the level of drug internalization. Notably, [Ag(EIA)2]Cl does not react with a few model proteins, but is capable of binding the C‐terminal dodecapeptide of thioredoxin reductase hTrxR(488–499) and to strongly inhibit the activity of this enzyme. Binding occurs through an unconventional process leading to covalent binding of one or two carbene ligands to the C‐terminal dodecapeptide with concomitant release of the silver cation. To the best of our knowledge, this mode of interaction is reported here for the first time for Ag(NHC)2 complexes. Stable and cytotoxic: A novel fluorescent silver(I) N‐heterocyclic carbene (NHC) complex was synthesized and characterized. This complex is highly stable and unreactive toward common model proteins, but is able to inhibit thioredoxin reductases. It is highly cytotoxic in neuroblastoma cancer cells, and its pharmacological action is likely related to an unconventional mechanism of binding to thioredoxin reductases.