The solution behavior of auranofin, EtPAuCl and EtPAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward representative colorectal cancer cell lines were found to be strong and similar in the three cases and a good correlation could be established between the cytotoxicity and the ability to inhibit thioredoxin reductase; remarkably, acute toxicity experiments for EtPAuI confirmed that, similarly to auranofin, this drug is well tolerated in a murine model. Overall, a very similar profile emerges for EtPAuI and EtPAuCl, which retain the potent cytotoxic effects of auranofin while showing some peculiar features. These results demonstrate that the presence of the thiosugar moiety is not mandatory for the pharmacological action, suggesting that the tuning of some relevant chemical properties such as lipophilicity could be exploited to improve bioavailability, with no loss of the pharmacological effects.
Although ferrocene derivatives have attracted considerable attention as possible anticancer agents, the medicinal potential of diiron complexes has remained largely unexplored. Herein, we describe the straightforward multigram‐scale synthesis and the antiproliferative activity of a series of diiron cyclopentadienyl complexes containing bridging vinyliminium ligands. IC50 values in the low‐to‐mid micromolar range were determined against cisplatin sensitive and resistant human ovarian carcinoma (A2780 and A2780cisR) cell lines. Notable selectivity towards the cancerous cells lines compared to the non‐tumoral human embryonic kidney (HEK‐293) cell line was observed for selected compounds. The activity seems to be multimodal, involving reactive oxygen species (ROS) generation and, in some cases, a fragmentation process to afford monoiron derivatives. The large structural variability, amphiphilic character and good stability in aqueous media of the diiron vinyliminium complexes provide favorable properties compared to other widely studied classes of iron‐based anticancer candidates.
The interaction of cyanines with nucleic acids is accompanied by intense changes of their optical properties. Consequently these molecules find numerous applications in biology and medicine. Since no detailed information on the binding mechanism of DNA/cyanine systems is available, a T-jump investigation of the kinetics and equilibria of binding of the cyanines Cyan40 [3-methyl-2-(1,2,6-trimethyl-4(1H)pyridinylidenmethyl)-benzothiazolium ion] and CCyan2 [3-methyl-2-[2-methyl-3-(3-methyl-2(3H)-benzothiazolylidene)-1-propenyl]-benzothiazolium ion] with CT-DNA is performed at 25 degrees C, pH 7 and various ionic strengths. Bathochromic shifts of the dye absorption band upon DNA addition, polymer melting point displacement (DeltaT = 8-10 degrees C), site size determination (n = 2), and stepwise kinetics concur in suggesting that the investigated cyanines bind to CT-DNA primary by intercalation. Measurements with poly(dA-dT).poly(dA-dT) and poly(dG-dC).poly(dG-dC) reveal fair selectivity of CCyan2 toward G-C basepairs. T-jump experiments show two kinetic effects for both systems. The binding process is discussed in terms of the sequence D + S left arrow over right arrow D,S left arrow over right arrow DS(I) left arrow over right arrow DS(II), which leads first to fast formation of an external complex D,S and then to a partially intercalated complex DS(I) which, in turn, converts to DS(II), a more stable intercalate. Absorption spectra reveal that both dyes tend to self-aggregate; the kinetics of CCyan2 self-aggregation is studied by T-jump relaxation and the results are interpreted in terms of dimer formation.
A Density Functional Theory (DFT) study of the absorbance and fluorescence emission characteristics of the cyanine thiazole orange (TO) in solution and when intercalated in DNA was carried out in combination with spectrophotometric and spectrofluorometric experiments under different conditions (temperature, concentration, solvent viscosity). T-jump relaxation kinetics of the TO monomer-dimer conversion enabled the thermodynamic parameters of this process to be evaluated. The overall data collected provided information on the features of the "light-switch" by the fluorescent TO and the comparison between experimental and calculated photo-physical properties allowed us to explain and rationalize both shifts and quenching/enhancing effects on fluorescence due to solvation, dimerisation and intercalation in the DNA.
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