Donor Atom Preference of Organoruthenium and Organorhodium Cations on the Interaction with Novel Ambidentate (N,N) and (O,O) Chelating Ligands in Aqueous Solution

Two novel, pyridinone-based chelating ligands containing separated (O,O) and (Namino,Nhet) chelating sets (Namino = secondary amine; Nhet = pyrrole N for H(L3) (1-(3-(((1H-pyrrole-2-yl)methyl)amino)propyl)-3-hydroxy-2-methylpyridin-4(1H)-one) or pyridine N for H(L5) (3-hydroxy-2-methyl-1-(3-((pyridin-2-ylmethyl)amino)propyl)pyridin-4(1H)-one)) were synthesized via reduction of the appropriate imines. Their proton dissociation processes were explored, and the molecular structures of two synthons were assessed by X-ray crystallography. These ambidentate chelating ligands are intended to develop Co(III)/PGM (PGM = platinum group metal) heterobimetallic multitargeted complexes with anticancer potential. To explore their metal ion binding ability, the interaction with Pd(II), [(η6-p-cym)Ru]2+ and [(η5-Cp*)Rh]2+ (p-cym = 1-methyl-4-isopropylbenzene, Cp* = pentamethyl-cyclopentadienyl anion) cations was studied in aqueous solution with the combined use of pH-potentiometry, NMR and HR ESI-MS. In general, organorhodium was found to form more labile complexes over ruthenium, while complexation of the (N,N) chelating set was slower than the processes of the pyridinone unit with (O,O) coordination. Formation of the organoruthenium complexes starts at lower pH (higher thermodynamic stabilities of the corresponding complexes) than for [(η5-Cp*)Rh]2+ but, due to the higher affinity of [η6-p-cym)Ru]2+ towards hydrolysis, the complexed ligands are capable of competing with hydroxide ion in a lesser extent than for the rhodium systems. As a result, under biologically relevant conditions, the rhodium binding effectivity of the ligands becomes comparable or even slightly higher than their effectivity towards ruthenium. Our results indicate that H(L3) is a less efficient (N,N) chelator for these metal ions than H(L5). Similarly, due to the relative effectivity of the (O,O) and (N,N) chelates at a 1:1 metal-ion-to-ligand ratio, H(L5) coordinates in a (N,N) manner to both cations in the whole pH range studied while, for H(L3), the complexation starts with (O,O) coordination. At a 2:1 metal-ion-to-ligand ratio, H(L3) cannot hinder the intensive hydrolysis of the second metal ion, although a small amount of 2:1 complex with [(η5-Cp*)Rh]2+ can also be detected.

Endogenous Opioid Levels Do Not Correlate With Itch Intensity and Therapeutic Interventions in Hepatic Pruritus

Background: Chronic pruritus affects up to 70% of patients with immune-mediated hepatobiliary disorders. Antagonists of the μ-opioid receptor (MOR) and agonists of the κ-opioid receptor (KOR) are used to treat hepatic itch, albeit with limited success. An imbalance between ligands of MOR and KOR receptors has recently been suggested as a potential mechanism of hepatic pruritus. In this study, we therefore investigated systemic levels of important endogenous opioids such as β-endorphin, dynorphin A, Leu- and Met-enkephalin in plasma of a large cohort of well-characterized patients with immune-mediated cholestatic disorders, including patients with liver cirrhosis, and during effective anti-pruritic therapy.Methods: Plasma samples and clinical data were prospectively collected from well-characterized patients with primary/secondary sclerosing cholangitis (PSC/SSC), primary biliary cholangitis (PBC) and overlap syndromes suffering from pruritus (n = 29) and age-, gender- and disease-matched controls without pruritus (n = 27) as well as healthy controls (n = 20). General laboratory testing for hepatobiliary and renal function was performed. Levels of β-endorphin, dynorphin A, Leu- and Met-enkephalin were quantified in plasma by ELISA. Intensity of pruritus over the last week was evaluated using a visual analog scale (VAS, 0–10).Results: PBC and PSC patients with or without pruritus did neither differ in disease entity, disease stage, nor in the presence of cirrhosis. While both dynorphin A and β-endorphin concentrations were lower in pruritic patients compared to those without pruritus and healthy controls, the MOR/KOR ligand ratio was unaltered. No significant differences were observed for Leu- and Met-enkephalin concentrations. Opioid levels correlated with neither itch intensity nor stage of disease. Cirrhotic patients displayed higher concentrations of MOR agonist Leu-enkephalin and KOR agonist dynorphin A. Endogenous opioid levels remained largely unchanged after successful treatment with the potent anti-pruritic drugs rifampicin and bezafibrate.Conclusions: Endogenous opioid levels and the MOR/KOR ligand ratio neither correlate with itch intensity nor differentiate pruritic from non-pruritic patients with immune-mediated liver diseases. Thus, endogenous opioids may modulate signaling pathways involved in hepatic pruritus, but are unlikely to represent the major pruritogens in liver disease.

Lipid Nanoparticle-Mediated Lymphatic Delivery of Immunostimulatory Nucleic Acids

Lymphatic delivery of a vaccine can be achieved using a dendritic cell (DC)-targeted delivery system that can cause DC to migrate to lymph nodes upon activation by an adjuvant. Here, we designed a mannose-modified cationic lipid nanoparticle (M-NP) to deliver the nucleic acid adjuvant, polyinosinic:polycytidylic acid (PIC). PIC-loaded M-NP (PIC/M-NP) showed stable lipoplexes regardless of the ligand ratio and negligible cytotoxicity in bone marrow-derived DC. DC uptake of PIC/M-NP was demonstrated, and an increased mannose ligand ratio improved DC uptake efficiency. PIC/M-NP significantly promoted the maturation of bone marrow-derived DC, and local injection of PIC/M-NP to mice facilitated lymphatic delivery and activation (upon NP uptake) of DC. Our results support the potential of PIC/M-NP in delivering a nucleic acid adjuvant for the vaccination of antigens.

Dinuclear Helicate or Mononuclear Pincer Lanthanide Complexes from One Ligand: Stereo-Controlled Assembly and Catalysis

By varying the metal/ligand ratio, either dinuclear triple helicates (ΛΛ/ΔΔ-La2LR/S 3) or mononuclear pincer complexes (Λ/Δ-LaLR/S) can be stereo-selectively obtained from the same chiral bistridentate ligand (LR/S). Due to the...

A Study of 1-Phenyl-3-Methyl-4-Trichloroacetyl Pyrazolone-5 as an Extractant for Uranium (VI) From Buffered Solutions

Chloroform solutions of 1-Phenyl-3-Methyl-4-Trichloroacetylpyrazolone-5 (HTCP) for the extraction of Uranium (VI) (UO22+) from various buffered solutions containing different SO42- ion concentrations was investigated. After extraction processes, colorimetric method was used to determine Uranium(VI) concentrations in aqueous media. Solutions of HTCP in chloroform did not extract U(VI) in buffered solutions containing SO42- ions between pH 0 – 2, which was attributed to the formation of unextractable Sulphate Uranyl (UO2)SO4 complex. However, there was extraction of U(VI) of 88,70 %, 76.84 % and 55.49 % between pH 2.96 – 3.21 for solutions containing 0.01 M, 0.1 M and 1 M SO42- ion respectively. An increase in SO42- ion concentration decreased the optimum extraction of U(VI). The presence of SO42- ion in buffered solutions had a masking effect on the extraction of U(VI). The metal ligand ratio was 1:1 and the adduct complex of the metal characterized as UO2(TCP) was extracted.