Profiling primaquine metabolites in primary human hepatocytes using UHPLC‐QTOF‐MS with 13C stable isotope labeling

Therapeutic efficiency and hemolytic toxicity of primaquine (PQ), the only drug available for radical cure of relapsing vivax malaria are believed to be mediated by its metabolites. However, identification of these metabolites has remained a major challenge apparently due to low quantities and their reactive nature. Drug candidates labeled with stable isotopes afford convenient tools for tracking drug‐derived metabolites in complex matrices by liquid chromatography‐tandem mass spectrometry (LC‐MS‐MS) and filtering for masses with twin peaks attributable to the label. This study was undertaken to identify metabolites of PQ from an in vitro incubation of a 1:1 w/w mixture of ¹³C₆‐PQ/PQ with primary human hepatocytes. Acquity ultra‐performance LC (UHPLC) was integrated with QTOF‐MS to combine the efficiency of separation with high sensitivity, selectivity of detection and accurate mass determination. UHPLC retention time, twin mass peaks with difference of 6 (originating from ¹³C₆‐PQ/PQ), and MS‐MS fragmentation pattern were used for phenotyping. Besides carboxy‐PQ (cPQ), formed by oxidative deamination of PQ to an aldehyde and subsequent oxidation, several other metabolites were identified: including PQ alcohol, predictably generated by oxidative deamination of PQ to an aldehyde and subsequent reduction, its acetate and the alcohol's glucuronide conjugate. Trace amounts of quinone‐imine metabolites of PQ and cPQ were also detected which may be generated by hydroxylation of the PQ/cPQ quinoline ring at the 5‐position and subsequent oxidation. These findings shed additional light on the human hepatic metabolism of PQ, and the method can be applied for identification of reactive PQ metabolites generated in vivo in preclinical and clinical studies. Copyright © 2013 John Wiley & Sons, Ltd.     

two crystalline modifications of [Au(dien)Cl](ReO4)2: synthesis, structure, and thermal properties

Two crystalline modifications of a new [Au(dien)Cl](ReO₄)₂ complex are studied. The geometric characteristics of the [Au(dien)Cl]²⁺ complex cations are compared, and the way of additional coordination of gold atomos is considered. The thermal properties of the compound are studied in the inert and reducing atmospheres, and for the first time the possibility of the formation of Au_0.1Re_0.9 solid solution based on the hcp lattice of Re is shown.     

Oppositely charged polyelectrolytes grafted onto planar surface: Mean-field lattice theory

Equilibrium structures of planar polyelectrolyte brushes formed by grafted chains carrying charges of opposite sign are examined by employing mean-field lattice theory. Two brushes of different architecture are considered: one formed by grafted diblock copolymers with oppositely charged blocks and the other being a mixed brush composed of oppositely charged homopolymers. The systems display nontrivial intrinsically inhomogeneous brush structures originating from the chain connectivity and the electrostatic interaction among the segments. In addition, a coexistence of stretched and coiled chains inside the brush is observed. The influence of the charges of the blocks, the relative length of the oppositely charged blocks, and the ionic strength of the solution on the brush inhomogeneity and structural differences between the two types of brushes are discussed. Received 14 March 2001 and Received in final form 18 June 2001     

Polyelectrolyte brushes with specific charge distribution: Mean-field lattice theory

A novel polymer system containing charged diblock polymers grafted onto a planar surface, simple salt and solvent has been considered in the framework of a mean-field lattice theory. On the basis of predicted volume fraction profiles of polymer segments, free ends, block junctions, and small ions, a detailed picture of the system has emerged. It is found that the structure of the polymer brush is decisively dependent of the relative charge of the blocks. For certain conditions, bimodal profiles appear which demonstrate the simultaneous presence of two types of chain conformations, one coiled and one stretched. Received 30 August 2000     

Refinement of the (NH4)2Na[Rh(NO2)6] Crystal Structure

The crystal structure of (NH₄)₂Na[Rh(NO₂)₆] previously studied only from the data on polycrystals is refined. The selection of the Fm-3 space group is shown to be unambiguous. Geometrical characteristics of the complex [Rh(NO₂)₆]^3s-anion are: Rh—N 2.051 ?, N-O 1.237 ?, ∠O-N-O 119.0°.     

Structure and Thermal Properties of [Rh(NH3)5Cl](WO4)x(MoO4)1s-x (x = 0, 0.5, 1)

The isostructurality of [Rh(NH₃)₅Cl](WO₄) _x (MoO₄)_1s-x (x = 0, 0.5, 1) complex salts is shown, and their thermal properties are compared. In a hydrogen atmosphere, transformations begin at T ∼ 200°C. According to the powder XRD data, the phase composition of the end products is markedly different. For the Rh—Mo system, the dependence (V/Z) of the atomic volume on the composition is presented. The thermal decomposition product [Rh(NH₃)₅Cl](MoO₄) (T _fin = 800°C) is shown to be the disordered Mo_0.5Rh_0.5 solid solution (a = 2.757(2) ?, c = 4.428(4) ?, P6₃/mmc space group).     

Crystal structure of [Rh(Thio)6](NO3)3·3H2O and [Pd(Thio)4](NO3)2 thiourea complexes — products of extraction tretament of rhodium(III) and palladium(II) nitrate-nitrite solutions

The products of the extraction treatment of Rh(III) and Pd(II) nitrate-nitrite solutions are studied. The [Rh(Thio)₆](NO₃)₃·3H₂O and [Pd(Thio)₄](NO₃)₂ complex salts are extracted and an X-ray diffraction analysis of single crystals is performed (BRUKER X8 APEX automated diffractometer, MoK _a radiation, graphite monochromator, two-dimensional CCD-detector). [Rh(Thio)₆](NO₃)₃·3H₂O crystallographic characteristics are as follows: _a = 15.1857(3) ?, _b = 10.7292(2) ?, _c = 18.8524(4) ?, β = 105.165(1)°, P2 ₁ /c space group, _Z =4; [Pd(Thio)₄](NO₃)₂: a = 5.8013(4) ?, b = 7.0981(5) ?, c = 11.4991(8) ?, α = 99.963(2)°, β = 101.410(2)°, γ = 102.229(2)°, P —1 space group, Z = 1.     

Protein-like copolymers: Computer simulation

The model ofAB copolymers with a “protein-like” primary sequence was developed. This type of copolymers was obtained in a computer experiment. First, the conformation of a collapsed dense homopolymer globule was generated and then, based on this conformation, the primaryAB sequence was determied by denoting the monomeric units located near the surface of the globule as unitsA and those constituting the core of the globule as unitsB. After that, the primary structure of the chain was fixed, and different interaction potentials for theA andB units were introduced. Drawing an analogy of this model to aqueous solutions of globular proteins,A units were interpreted as hydrophilic, andB units were regarded as hydrophobic. By means of Monte Carlo simulation using the bond fluctuation model, the coli—globule transition in “protein-like”AB copolymer, induced by an increase in the attraction between the hydrophobicB units, was studied. The coil—globule transition in a copolymer with the “protein-like” primary sequence occurs at a higher temperature and has higher rate and is sharper than that in a random copolymer with the sameA/B composition and in a random block copolymer with the sameA/B composition and the same “degree of blockiness”. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 884–889, May, 1998.     

Structure of the first nitrosoammine complexes of ruthenium with a coordinated sulfate ion: [Ru(NO)(NH3)4(SO4)](HSO4)·H2O and [Ru(NO)(NH3)3Cl(SO4)]·2H2O

We present a thermogravimetric study of the thermolysis of trans-[Ru(NO)(NH₃)₄(H₂O)](HSO₄)SO₄ in a helium atmosphere. The intermediate product of thermolysis (at 186°C) is treated with a 2 M H₂SO₄ solution to obtain the first example of a sulfate ammine complex of nitrosoruthenium [Ru(NO)(NH₃)₄(SO₄)](HSO₄)·H₂O (I) with a ∼70% yield. The product of higher temperature thermolysis (220°C) is treated with acids (H₂SO₄ and HCl) to obtain a triammine complex [Ru(NO)(NH₃)₃Cl(SO₄)]·2H₂O (II). The structure of the compounds is found by single crystal XRD: Pna2₁ space group, a = 10.8005(2) ?, b = 14.9032(3) ?, c = 7.7603(1) ?) (I) and P2_1/n space group, a = 8.9397(1) ?, b = 8.3276(1) ?, c = 13.8993(2) ?; β = 97.358(1)° (II).     

Two crystalline modifications of Pd<Subscript>2</Subscript>(μ-ac)<Subscript>2</Subscript>(acac)<Subscript>2</Subscript>

Crystal structures of two modifications of a binuclear Pd₂(μ-ac)₂(acac)₂ complex are studied at 150 K and 297 K (ac = acetate; acac = acetylacetonate). It is demonstrated that in both cases, the packing of the complexes can be considered as pseudohexagonal, the molecules forming infinite chains by interactions between chelate rings with the shortest contacts Pd...C _γ ～ 3.3 Å.