Abstract
A series of gold(I) triphenylphosphine (PPh3) complexes (1–9) involving 2-chloro-N6-(substituted-benzyl)adenine derivatives as N-donor ligands was synthesized and thoroughly characterized by relevant methods, including electrospray-ionization (ESI) mass spectrometry and multinuclear NMR spectroscopy. The anti-inflammatory and antiedematous effects of three representatives 1, 5 and 9 were evaluated by means of in vitro model based on the expression of pro- and anti-inflammatory cytokines and influence of the complexes on selected forms of matrix metalloproteinases secreted by LPS-activated THP-1 monocytes and in vivo model evaluating the antiedematous effect of the complexes in the carrageenan-induced rat hind-paw edema model. In addition to the pharmacological observations, the affected hind paws were post mortem subjected to histological and immunohistochemical evaluations. The results of both in vivo and ex vivo methods revealed low antiedematous and anti-inflammatory effects of the complexes, even though the in vitro model identified them as promising anti-inflammatory acting compounds. The reason for this discrepancy lies probably in low stability of the studied complexes in biological environment, as demonstrated by the solution interaction studies with sulfur-containing biomolecules (cysteine and reduced glutathione) using the ESI mass spectrometry.
Highlights
The mixed-ligand gold(I) complexes, involving the derivatives of phosphine, are in the scope of chemists for several reasons
The ability of gold(I) species to interact with the active site of thioredoxin reductase can be clarified sufficiently by the application of the Pearson’s principle of hard and soft acids and bases, while the gold(I) species as a soft acid tend to bind with the soft base ligands [19]
The gold(I) complexes of the general formula [Au(Ln)(PPh3)] (1–9) involving deprotonated 2-chloro-N6-(substitutedbenzyl)adenine derivatives (Ln) coordinated through the N9 atom, and PPh3 molecule coordinated to the central atom through its phosphorus atom were prepared and characterized
Summary
The mixed-ligand gold(I) complexes, involving the derivatives of phosphine, are in the scope of chemists for several reasons. The ability of gold(I) species to interact with the active site of thioredoxin reductase can be clarified sufficiently by the application of the Pearson’s principle of hard and soft acids and bases, while the gold(I) species as a soft acid tend to bind with the soft base ligands [19]. It prefers the binding to selenolate groups of TrxR, subsequently leading to the inhibition of its activity both in cytosol and mitochondria, leaving the similar system of glutahione reductase, containing the thiolate groups in the active site, unaffected [19,22] up to high concentrations. It has been found that Auranofin inhibits TrxR in a p53independent manner [23]
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