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With the aim of assessing whether Au(iii) compounds with pincer type ligands might be utilized as potential antitumor agents, three new monofunctional Au(iii) complexes of the general formula [Au(N-N'-N)Cl]Cl2, where N-N'-N = 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine (H2LtBu, 1), 2,6-bis(5-tert-butyl-1-methyl-1H-pyrazol-3-yl)pyridine (Me2LtBu, 2) or 2,6-bis((4S,7R)-1,7,8,8-tetramethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine (Me2*L, 3) were synthesized. All complexes were characterized by elemental analysis, spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR) and mass spectrometry (MALDI TOF MS). The chemical behavior of the complexes under physiological conditions was studied by UV-Vis spectroscopy, which showed that all compounds were remarkably stable and that the gold center remained in the 3+ oxidation state. The kinetics and the mechanism of the reaction of complexes 1-3 with guanine derivatives (i.e. guanosine (Guo) and guanosine-5'-monophosphate (5'-GMP)) and calf thymus DNA (CT DNA) were studied by stopped-flow spectroscopy. The three complexes displayed moderately different rate constants in their reactions with Guo, 5'-GMP and CT DNA, which can be explained by the steric hindrance and σ-donicity of the methyl substituent on the bis-pyrazolylpyridine fragment in complexes 2 and 3. The measured enthalpies and entropies of activation (ΔH≠ > 0, ΔS≠ < 0) supported an associative mechanism for the substitution process. The interaction of the newly synthesized complexes 1-3 with CT DNA was investigated by UV-Vis and fluorescence spectroscopy, and also by viscosity measurements, which all indicated that complexes 1-3 bound to CT DNA with moderate binding affinity (Kb = 1.6-5.7 × 103 M-1) and stabilized the duplex of CT DNA. Molecular docking indicated that complexes 1-3 interacted with DNA via intercalation. Complex 1 reduced the cell survival of all the investigated cell lines (A549, A375, and LS-174) with IC50 values being up to 20 μM. We have shown that 1 induced perturbations of the cell cycle and led to apoptosis in human melanoma A375 cells. Complex 1 also affected the level of reactive oxygen species (ROS) in the same cells. However, pre-treatment of A375 cells with NAC (ROS scavenger) reversed the effect of 1 on their survival.

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The two new heterometallic Ru­(II)-tpy/ferrocene complexes [Ru­(tpy)­Cl2(mtefc)] (1) and [Ru­(tpy)­Cl2(mtpfc)] (2) (where tpy = 2,2′:6′,2′′-terpyridine, mtefc = (2-(methylthio)­ethyl)­ferrocene, and mtpfc = (3-(methylthio)­propyl)­ferrocene) have been synthesized and then characterized through elemental analysis, followed by various spectroscopic (IR, UV–vis, 1D and 2D NMR) and mass spectrometric techniques (MALDI TOF and ESI Q-TOF MS). UV–vis and fluorescence spectroscopy and viscometry were employed to study the interactions of the complexes 1 and 2 with calf thymus DNA. Both 1 and 2 expelled ethidium bromide (EB) from the EB/DNA complex (K sv = (1.5–1.8) × 104 M–1), which suggested that the complexes intercalated into the double helix of DNA. Both complexes strongly quenched the fluorescence of tryptophan residues in serum albumin through both static and dynamic quenching. Molecular docking confirmed the intercalative mode of complex interaction with DNA. The docking results implied that 1 and 2 interacted with hydrophobic residues of albumin, particularly with those lying in the proximity of Tyr 160. We here demonstrate the high cytotoxic potential of complexes 1 and 2 against the breast cancer cells that originated either from humans (MDA-MB-231) or from mice (4T1), with apoptosis being the main mechanism of complex-induced cell death. It is worth noting that both complexes promoted activation of innate and acquired antitumor immunity, which contributed to the reduced growth and progression of mammary carcinoma in vivo.

The aim of this study was to examine changes in some hormones concentrations in calves during the first 32 hours of neonatal life and to estimate their association with glycemia. Thyrty two Holstein breed calves were selected for the study. Blood samples were taken at 30, 60 and 90 minutes postnatal. Calves received pooled colostrum: primary colostum (1.5 L, 2 hours after birth), secondary colostrum (2 L, 14 hours after birth) and tertiary colostrum (2 L, 26 hours after birth). Blood samples were taken at hours 5, 20 and 32 of neonatal life. Concentrations of glucose, insulin, cortisol, thyroid hormones and IGF-I and abundance of IGFBP-1, IGFBP-2 and IGFBP-3 were determined in the blood serum. The T3/T4 ratio was also calculated. Calves were born hypoglycemic (glycemia was 2.56±1.05 mmol/L at birth). Thereafter, glycemia significantly increased (p<0.001) to 3.05±0.89 mmol/L at min 90. Glucose concentration showed a further increase after colostrum intake and was significantly higher than at the initial value in all examined periods (p<0.001). During the first 90 minutes of neonatal life insulinemia decreased significantly (p<0.001) compared to initial value (26.33±10.05 μIU/L) and it measured 18.66±5.56 μIU/L at min 90. Cortisolemia was highest at minute 30 (85.08±19.36 nmol/L) and than decreased until the end of the experiment (p<0.001) compared to initial values in samples obtained during the period of colostrum intake. A significantly high correlation was determined between glycemia and cortisolemia in all examined periods before the first colostrums intake (r2=0.854; p<0.01 at min 30; r2=0.742; p<0.01 at min 60 and r2=0.551; p<0.01 at min 90). T4 concentrations significantly increased during the first 2 hours, while T3 concentrations decreased, significantly from min 30 to min 90 postnatal (p<0.05). T3/T4 ratio significantly increased during the first 2 hours of neonatal life. After first colostrum intake, concentrations of both hormones rose significantly compared to the initial level, but T3/T4 ratio did not change and maintained the value determined at minute 90. IGF- 1 concentrations significantly decreased during the first 2 postnatal hours. A significant positive correlation was observed between IGF-1 concentration and insulinemia (r2=0.463; p<0.05 at min 30, r2=0.662; p<0.01 at min 60 and r2=0.583; p<0.01 at min 90). IGFBP-3 abundance significantly decreased, while IGFBP-1 significantly increased in this period. IGFBP-2 abundance was highest at birth. Results presented in this study indicate that the increase in glucose concentration during the first 2 hours of neonatal life, before the first colostrum intake is mainly the result of increased activity of the adrenal cortex in cortisol secretion and extrathyroidal tissue thus providing sufficient triiodothyronine. Immaturity of mechanisms responsible for insulin secretion provides the dominance of catabolic processes. Changes of the IGF system provide a rise of glucose concentration...

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