Abstract
A series of gold(I) and silver(I) derivatives with N- or S-donor ligands derived from 2-anilinopyridine has been synthesized and characterized. The mononuclear structure of [Au(L1)(PPh3)](TfO) (1a) and [Au(L2)(PPh3)](TfO) (1b) was confirmed by X-ray diffraction studies, as well as the dinuclear structure in the case of [Ag(TfO)(L1)]2 (4a). Most of the complexes are cytotoxic against a model of colorectal adenocarcinoma (Caco-2 cell line) and breast adenocarcinoma cancer cell lines (MCF-7). [Au(L1)(PPh3)](TfO) (1a) was able to induce caspases 8 and 3 activation, loss of mitochondrial membrane potential, and reactive oxygen species (ROS)-dependent cell death on Caco-2 cells upon 24 h incubation. In addition, the gold complex 1a produced a significant inhibition of the redox enzyme thioredoxin reductase as well as 20S proteasome. However, the silver(I) analogue, [Ag(TfO)(L1)(PPh3)] (2a), induced cell death independent of inhibition of thioredoxin reductase and 20S proteasome, triggered ROS-independent apoptosis mediated by caspase 8 and 3 activation, and loss of mitochondrial membrane potential, which points to a different mechanism of action for both derivatives, dependent on the metal center.
Highlights
The use of platinum-based anticancer drugs in chemotherapy is accompanied with the presence of side-effects such as gastrointestinal and hematological toxicity in addition to drug-resistance phenomena.[1,2] In order to circumvent these drawbacks new metallodrugs have been designed based in non-platinum metals, such as ruthenium or gold.Gold complexes interact with cellular proteins[3,4,5] instead of DNA, the main target of the platinum-based complexes, which suppose an important advantage in order to overcome the limitations found in platinum derivatives
The asymmetric sulfonyl stretching frequencies characteristic of ionic triflate group[55] are observed in the IR spectra of both gold complexes (1a-b), which is corroborated in their 19F{1H} NMR with a singlet centered at -80 ppm
A downfield displacement of the pyridine resonances next to the carbonyl moiety is observed in the 1H NMR spectra of complexes 1a and 2a, which is in accordance with the coordination of the AuPPh3 moiety through the N atom of that pyridine
Summary
The use of platinum-based anticancer drugs in chemotherapy is accompanied with the presence of side-effects such as gastrointestinal and hematological toxicity in addition to drug-resistance phenomena.[1,2] In order to circumvent these drawbacks new metallodrugs have been designed based in non-platinum metals, such as ruthenium or gold. The mechanism of action of silver derivatives has not been fully clarified, it involves the release of the silver ion inside the cell that disrupts its function.[38] the choice of the ligands that can strongly coordinate the metallic center and facilitate the slow release of Ag+ is essential With this idea, a significant amount of silver complexes with a great variety of ligands has been designed for potential pharmaceutical usage.[16, 18,19, 21] silver N-heterocyclic carbene (NHC) complexes 15, 17, 22-24,39 constitute the group with the largest number of examples of Ag(I) compounds with biological properties, mainly due to their strong coordination to the metallic center and their increased stability. Measurement of reactive oxygen species (ROS) and cell death studies have been performed
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