RESUMO
Gold complexes with N-heterocyclic carbene (NHC) ligands have been attracting major attention in medicinal inorganic chemistry based on their favorable antiproliferative effects and the structural versatility of the coordinated NHC ligands. Here we present a novel complex of the type (NHC)2Au+, which represents a substantially improved and selective TrxR inhibitor compared to close structural analogues. The complex is highly stable in various solutions over 96 hours, however, comparative cellular uptake studies indicate metabolic transformations inside cells over time. A portfolio of other gold complexes (e.g. Auranofin) has been used as references in key biological assays, showing that the novel (NHC)2Au+ complex exhibits substantially lower protein binding in combination with a strongly enhanced cytotoxic activity.
Assuntos
Antineoplásicos , Inibidores Enzimáticos , Ouro/química , Metano/análogos & derivados , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/química , Humanos , Metano/química , Modelos Moleculares , Ligação ProteicaRESUMO
A series of gold(i) complexes with two N-heterocyclic carbene ligands (biscarbene gold complexes) were prepared and evaluated for their effects against cancer cells and pathogenic bacteria. Proliferation inhibition was observed in cancer cells and in Gram-positive bacteria, whereas Gram-negative bacteria were less sensitive towards the compounds. The protein binding and cellular uptake were quantified and the combined results indicated a strong correlation between cellular bioavailability and antiproliferative effects. The biscarbene gold complexes inhibited bacterial and mammalian TrxRs with low to moderate potency. However, based on the obtained structure-activity-relationships and the high cellular accumulation levels, TrxR inhibition can be considered as a relevant contributor to the cellular pharmacology of biscarbene gold(i) complexes.
RESUMO
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.
Assuntos
Complexos de Coordenação/química , DNA/química , Substâncias Intercalantes/química , Metano/análogos & derivados , Naftalimidas/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dicroísmo Circular , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Cristalografia por Raios X , Cimenos , DNA/metabolismo , Estabilidade de Medicamentos , Células HT29 , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/toxicidade , Ligantes , Células MCF-7 , Metano/química , Conformação Molecular , Monoterpenos/química , Ródio/química , Rutênio/química , Espectrofotometria UltravioletaRESUMO
Gold complexes with N-heterocyclic carbene (NHC) ligands represent a promising class of metallodrugs for the treatment of cancer or infectious diseases. In this report, the synthesis and the biological evaluation of halogen-containing NHC-AuI -Cl complexes are described. The complexes 1 and 5 a-5 f displayed good cytotoxic activity against tumor cells, and cellular uptake studies suggested that an intact Au-NHC fragment is essential for the accumulation of high amounts of both the metal and the NHC ligand. However, the bioavailability was negatively affected by serum components of the cell culture media and was influenced by likely transformations of the complex. One example (5 d) efficiently induced apoptosis in vincristine- and daunorubicin-resistant P-glycoprotein overexpressing Nalm-6 leukemia cells. Cellular uptake studies with this compound showed that both the wild-type and resistant Nalm-6 cells accumulated comparable amounts of gold, indicating that the gold drug was not excreted by P-glycoprotein or other efflux transporters. The effective inhibition of mammalian and bacterial thioredoxin reductases (TrxR) was confirmed for all of the gold complexes. Antibacterial screening of the gold complexes showed a particularly high activity against Gram-positive strains, reflecting their high dependence on an intact Trx/TrxR system. This result is of particular interest as the inhibition of bacterial TrxR represents a relatively little explored mechanism of new anti-infectives.
