Iron Overload in Children with Acute Lymphoblastic and Acute Myeloblastic Leukemia-Experience of One Center.

Transfusions of packed red blood cells (PRBCs), given due to an oncological disease and its acute complications, are an indispensable part of anticancer therapy. However, they can lead to post-transfusion iron overload. The study aim was to evaluate the role of ferritin as a nonspecific marker of leukemic growth and marker of transfusion-related iron overload. We performed a longitudinal study of PRBC transfusions and changes in ferritin concentrations during the oncological treatment of 135 patients with childhood acute lymphoblastic and acute myeloblastic leukemia (ALL and AML, median age 5.62 years). At the diagnosis, 41% of patients had a ferritin level over 500 ng/mL, and 14% of patients had a ferritin level over 1000 ng/mL. At the cessation of the treatment, 80% of the children had serum ferritin (SF) over 500 ng/mL, and 31% had SF over 1000 ng/mL. There was no significant difference between SF at the beginning of the treatment between ALL and AML patients, but children with AML finished treatment with statistically higher SF. AML patients had also statistically higher number of transfusions. We found statistically significant positive correlations between ferritin and age, and weight and units of transfused blood. Serum ferritin at the moment of diagnosis can be a useful marker of leukemic growth, but high levels of SF are connected with iron overload in both AML and ALL.

Synthesis, Crystal Structures, Lipophilic Properties and Antimicrobial Activity of 5-Pyridylmethylidene-3-rhodanine-carboxyalkyl Acids Derivatives.

The constant increase in the resistance of pathogenic bacteria to the commonly used drugs so far makes it necessary to search for new substances with antibacterial activity. Taking up this challenge, we obtained a series of rhodanine-3-carboxyalkyl acid derivatives containing 2- or 3- or 4-pyridinyl moiety at the C-5 position. These compounds were tested for their antibacterial and antifungal activities. They showed activity against Gram-positive bacteria while they were inactive against Gram-negative bacteria and yeast. In order to explain the relationship between the activity of the compounds and their structure, for selected derivatives crystal structures were determined using the X-ray diffraction method. Modeling of the isosurface of electron density was also performed. For all tested compounds their lipophilicity was determined by the RP-TLC method and by calculation methods. On the basis of the carried-out research, it was found that the derivatives with 1.5 N···S electrostatics interactions between the nitrogen atom in the pyridine moiety and the sulfur atom in the rhodanine system showed the highest biological activity.

Significance of Specific Oxidoreductases in the Design of Hypoxia-Activated Prodrugs and Fluorescent Turn off-on Probes for Hypoxia Imaging.

Hypoxia is one of the hallmarks of the tumor microenvironment and can be used in the design of targeted therapies. Cellular adaptation to hypoxic stress is regulated by hypoxia-inducible factor 1 (HIF-1). Hypoxia is responsible for the modification of cellular metabolism that can result in the development of more aggressive tumor phenotypes. Reduced oxygen concentration in hypoxic tumor cells leads to an increase in oxidoreductase activity that, in turn, leads to the activation of hypoxia-activated prodrugs (HAPs). The same conditions can convert a non-fluorescent compound into a fluorescent one (fluorescent turn off-on probes), and such probes can be designed to specifically image hypoxic cancer cells. This review focuses on the current knowledge about the expression and activity of oxidoreductases, which are relevant in the activation of HAPs and fluorescent imaging probes. The current clinical status of HAPs, their limitations, and ways to improve their efficacy are briefly discussed. The fluorescence probes triggered by reduction with specific oxidoreductase are briefly presented, with particular emphasis placed on those for which the correlation between the signal and enzyme expression determined with biochemical methods is achievable.

Preliminary Studies of Antimicrobial Activity of New Synthesized Hybrids of 2-Thiohydantoin and 2-Quinolone Derivatives Activated with Blue Light.

Thiohydantoin and quinolone derivatives have attracted researchers' attention because of a broad spectrum of their medical applications. The aim of our research was to synthesize and analyze the antimicrobial properties of novel 2-thiohydantoin and 2-quinolone derivatives. For this purpose, two series of hybrid compounds were synthesized. Both series consisted of 2-thiohydantoin core and 2-quinolone derivative ring, however one of them was enriched with an acetic acid group at N3 atom in 2-thiohydantoin core. Antibacterial properties of these compounds were examined against bacteria: Staphylococcus aureus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. The antimicrobial assay was carried out using a serial dilution method to obtain the MIC. The influence of blue light irradiation on the tested compounds was investigated. The relative yield of singlet oxygen (1O2*, 1Δg) generation upon excitation with 420 nm was determined by a comparative method, employing perinaphthenone (PN) as a standard. Antimicrobial properties were also investigated after blue light irradiation of the suspensions of the hybrids and bacteria placed in microtitrate plates. Preliminary results confirmed that some of the hybrid compounds showed bacteriostatic activity to the reference Gram-positive bacterial strains and a few of them were bacteriostatic towards Gram-negative bacteria, as well. Blue light activation enhanced bacteriostatic effect of the tested compounds.

Influence of protonation on the geometry of 2-{[(2,6-dimethylphenoxy)ethyl]amino}-1-phenylethan-1-ol: crystal structures of the free base and of its chloride and 3-hydroxybenzoate salt forms.

The aroxyalkylaminoalcohol derivatives are a group of compounds known for their pharmacological action. The crystal structures of four new xylenoxyaminoalcohol derivatives having anticonvulsant activity are reported, namely, 2-{[2-(2,6-dimethylphenoxy)ethyl]amino}-1-phenylethan-1-ol, C18H23NO2, 1, the salt N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxy-1-phenylethan-2-aminium 3-hydroxybenzoate, C18H24NO2+·C7H5O3-, 2, and two polymorphs of the salt (R)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxy-1-phenylethan-2-aminium chloride, C18H24NO2+·Cl-, 3 and 3p. Both polymorphs crystallize in the space group P21212 and each has two cations and two anions in the asymmetric unit (Z' = 2). The molecules in the polymorphs show differences in their molecular conformations and intermolecular interactions. The crystal packing of neutral 1 is dominated by intermolecular O-H...N hydrogen bonds, resulting in the formation of one-dimensional chains. In the crystal structures of the salt forms (2, 3 and 3p), each protonated N atom is engaged in a charge-assisted hydrogen bond with the corresponding anion. The protonation of the N atom also influences the conformation of the molecular linker between the two aromatic rings and changes the orientation of the rings. The crystal packing of the salt forms is dominated by intermolecular O-H...O hydrogen bonds, resulting in the creation of chains and rings. Structural studies have been enriched by the calculation of Hirshfeld surfaces and the corresponding fingerprint plots.

The conformational analyses of 2-amino-N-[2-(dimethylphenoxy)ethyl]propan-1-ol derivatives in different environments.

Four crystal structures of 2-amino-N-(dimethylphenoxyethyl)propan-1-ol derivatives, characterized by X-ray diffraction analysis, are reported. The free base (R,S)-2-amino-N-[2-(2,3-dimethylphenoxy)ethyl]propan-1-ol, C13H21NO2, 1, crystallizes in the space group P21/n, with two independent molecules in the asymmetric unit. The hydrochloride, (S)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium chloride, C13H22NO2+·Cl-, 2c, crystallizes in the space group P21, with one cation and one chloride anion in the asymmetric unit. The asymmetric unit of two salts of 2-picolinic acid, namely, (R,S)-N-[2-(2,3-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C13H22NO2+·C6H4NO2-, 1p, and (R)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C13H22NO2+·C6H4NO2-, 2p, consists of one cation and one 2-picolinate anion. Salt 1p crystallizes in the triclinic centrosymmetric space group P-1, while salt 2p crystallizes in the space group P41212. The conformations of the amine fragments are contrasted and that of 2p is found to have an unusual antiperiplanar arrangement about the ether group. The crystal packing of 1 and 2c is dominated by hydrogen-bonded chains, while the structures of the 2-picolinate salts have hydrogen-bonded rings as the major features. In both salts with 2-picolinic acid, the specific R12(5) hydrogen-bonding motif is observed. Structural studies have been enriched by the generation of fingerprint plots derived from Hirshfeld surfaces.

High-pressure and theoretical studies reveal significant differences in the electronic structure and bonding of magnesium, zinc, and nickel ions in metalloporphyrinoids.

High pressure in combination with optical spectroscopy was used to gain insights into the interactions between Mg(2+), Zn(2+), and Ni(2+) ions and macrocyclic ligands of porphyrinoid type. In parallel, the central metal ion-macrocycle bonding was investigated using theoretical approaches. The symmetry properties of the orbitals participating in this bonding were analyzed, and pigment geometries and pressure/ligation effects were computed within DFT. Bacteriopheophytin a was applied as both a model chelator and a highly specific spectroscopic probe. The analysis of solvent and pressure effects on the spectral properties of the model Mg(2+), Zn(2+), and Ni(2+) complexes with bacteriopheophytin a shows that various chemical bonds are formed in the central pocket, depending on the valence configuration of the central metal ion. In addition, the character of this bonding depends on symmetry of the macrocyclic system. Since in most cases it is not coordinative bonding, these results challenge the conventional view of metal ion bonding in such complexes. In (labile) complexes with the main group metals, the metal ion-macrocycle interaction is mostly electrostatic. Significantly, water molecules are not preferred as a second axial ligand in such complexes, mainly due to the entropic constraints. The metal ions with a closed d shell may form (stable) complexes with the macrocycle via classical coordination bonds, engaging their p and s orbitals. Transition metals, due to the unfilled d shell, do form much more stable complexes, because of strong bonding via both coordination and covalent interactions. These conclusions are confirmed by DFT computations and theoretical considerations, which altogether provide the basis to propose a consistent and general mechanism of how the central metal ion and its interactions with the core nitrogens govern the physicochemical properties of metalloporphyrinoids.

[Transabdominal chorionic villus sampling (CVS) for prenatal diagnosis of chromosomal disorders--own experiences]. / Przezbrzuszna biopsja kosmówki w prenatalnej diagnostyce zaburzen chromosomowych--doswiadczenia wlasne.

OBJECTIVE: To present the authors' own experiences on transabdominal Chorionic Villus Sampling (CVS) for prenatal diagnosis of genetic disorders. DESIGN: Descriptive study PATIENS AND METHODS: A total of 290 couples with request for prenatal diagnosis of various genetic disorders were studied. The most common indications were: fetal abnormalities suspected in an ultrasound scan and biochemistry positive family history on genetic disorders, maternal age. Transabdominal CVS was done under local anesthesia and ultrasound guidance. The genetic analysis was possible in 264 cases (241 with abnormal ultrasound scan and/or biochemistry 11 with positive family history 12 with maternal age). Results were recorded and analyzed for descriptive statistics. RESULT: A total of 290 CVSs were done in the outdoor Most procedures (76%) were done between 12 and 14 weeks (range 11-16 weeks). All placental positions including both anterior and posterior were approachable through the trans-abdominal route. The overall success rate was 100%. Abnormal fetal karyotype was diagnosed in 39% of cases. In 12.9% of cases inconclusive results were observed (due to placental mosaicism or maternal cells contamination). More aneuploidies were observed in group with abnormal first trimester screening (us scan and/or biochemistry) compared to any other indications. CONCLUSION: Transabdominal CVS is a useful outdoor procedure for prenatal diagnosis. However indications for the procedure should be carefully considered since some risk of inconclusive results occurred.

[Chorionic Villus Sampling in cytogenetic analysis--disadvantages and advantages]. / Analiza cytogenetyczna biopsji kosmówki--wady i zalety.

Chorionic villus sampling is used in prenatal diagnosis, enabling to detect fetal genetic abnormalities. Its advantages include the possibility of performing the procedure during the first trimester of pregnancy relatively fast result, risk of miscarriage comparable to that in case of amniocentesis. The disadvantages of this method are: difficult cytogenetic analysis, the possibility of contamination with maternal cells and the risk of mosaicism. There should always be a valid indication to perform the CVS procedure.

Structural and electronic effects in the metalation of porphyrinoids. Theory and experiment.

The structure-reactivity relationships in metalation reactions of porphyrinoids have been studied using experimental and theoretical methods. A series of eight porphyrinoic ligands, derivatives of chlorophylls, was prepared in which both the peripheral groups and the degrees of saturation of the macrocycle were systematically varied. To reveal the solvent and structural factors which control the interactions of these macroligands with metal centers, their interactions with reactive Zn(2+) and inert Pt(2+) ions were investigated using absorption spectroscopy. In parallel, quantum chemical calculations (density functional theory, DFT) were performed for the same set of molecules to examine the influence of structural and electronic factors on the energy of the frontier orbitals, the nucleophilicity/electronegativity of the macrocycle, its hardness, and conformation. These static descriptors of chemical reactivity, relevant to metalation reactions, were verified against the results obtained in the experimental model. The experimentally obtained kinetic data clearly show that the solvent has a crucial role in the activation of the incoming metal center. In terms of chelator structure, the largest effects concern the size of the delocalized pi-electron system and the presence of side groups. Both the DFT calculations and experimental results show the strong influence of the macrocycle rigidity and of the peripheral groups on the chelating ability of porphyrinoids. In particular, the peripheral functionalization of the macrocyclic system seems to drastically reduce its reactivity toward metal ions. The effect of peripheral groups is two-fold: (i) a lower electron density on the core nitrogens, and (ii) increased rigidity of the macrocycle. The outcomes of the theoretical and experimental analyses are discussed also in terms of their relevance to the mechanism of biological metal insertion in the biosynthesis of heme and chlorophyll.

Understanding chlorophylls: central magnesium ion and phytyl as structural determinants.

Phytol, a C20 alcohol esterifying the C-17(3) propionate, and Mg2+ ion chelated in the central cavity, are conservative structural constituents of chlorophylls. To evaluate their intramolecular structural effects we prepared a series of metal- and phytyl-free derivatives of bacteriochlorophyll a and applied them as model chlorophylls. A detailed spectroscopic study on the model pigments reveals meaningful differences in the spectral characteristics of the phytylated and non-phytylated pigments. Their analysis in terms of solvatochromism and axial coordination shows how the central Mg and phytyl residue shape the properties of the pigment. Surprisingly, the presence/absence of the central Mg has no effect on the solvatochromism of (bacterio)chlorophyll pi-electron system and the hydrophobicity of phytyl does not interfere with the first solvation shell of the chromophore. However, both residues significantly influence the conformation of the pigment macrocycle and the removal of either residue increases the macrocycle flexibility. The chelation of Mg has a flattening effect on the macrocycle whereas bulky phytyl residue seems to control the conformation of the chromophore via steric interactions with ring V and its substituents. The analysis of spectroscopic properties of bacteriochlorophyllide (free acid) shows that esterification of the C-17(3) propionate is necessary in chlorophylls because the carboxyl group may act as a strong chelator of the central Mg. These observations imply that the truncated chlorophylls used in theoretical studies are not adequate as models of native chromophores, especially when fine effects are to be modeled.

Interplay between acetate ions, peripheral groups, and reactivity of the core nitrogens in transmetalation of tetrapyrroles.

The mechanism of acetate-assisted transmetalation of tetrapyrroles was investigated in a model system consisting of chlorophyll a and copper(II) acetate in organic solvents by using a spectroscopic and kinetic approach. Surprisingly, acetate ions bind to the central Mg in chlorophyll much more strongly than do acetonitrile, methanol and even pyridine, one of the best ligands in chlorophyllic systems. This exceptionally strong non-symmetrical axial ligation of the central Mg by acetate causes its out-of-plane displacement and deformation of the tetrapyrrole ring, thus facilitating the interaction with an incoming CuII complex. This mechanism is controlled by a keto-enol tautomerism of the chlorophyll isocyclic ring. Additionally, depending on solvent, acetate activates the incoming metal ions. These new insights allow to suggest a mechanism for the acetate method of metal exchange in tetrapyrrolic macrocycles, which resembles biological insertion of metal ions into porphyrins. It also provides a guideline for the design of more efficient methods for the metalation of porphyrins and related macrocycles.

Steric control of bacteriochlorophyll ligation.

The axial coordination of central Mg(2+) ion in chlorophylls is of great structural and functional importance for virtually all photosynthetic chlorophyll proteins; however, little thermodynamic data are available on the ligand binding to these pigments. In the present study, spectral deconvolution of the bacteriochlorophyll Q(X) band serves to determine the ligand binding equilibria and relationships between thermodynamic parameters of ligand binding, ligand properties, and steric interactions occurring within the pigment. On the basis of the temperature effects on coordination, DeltaH degrees, DeltaS degrees, and DeltaG degrees of binding various types of ligands (acetone, dimethylformamide, imidazole, and pyridine) to diastereoisomeric bacteriochlorophylls were derived from respective van't Hoff's plots. At ambient temperatures, only ligation by imidazole and pyridine occurs spontaneously while DeltaG degrees becomes positive for ligation by acetone and dimethylformamide, due to a relatively large entropic effect, which is dominating when the energetic effects of ligation are small. It reflects, in quantitative terms, the control of the equatorial coordination of the Mg(2+) ion via the axial coordination: a "hard" free Mg(2+) ion is made into a softer center through the coordination of tetrapyrrole. Pigment structural features have comparable effects on the energetic and entropic contributions to the difference of ligation free energy between the diastereoisomers of bacteriochlorophyll. DeltaS degrees and DeltaH degrees values are consistently lower for the S epimer, most likely due to the steric crowding between bulky substituents. The two epimers show a 5 J.mol(-1).K(-1) difference in DeltaS degrees values, regardless of the ligand type, while the difference in DeltaH degrees amounts to 1.7 kJ.mol(-1), depending on the ligand. Such steric control of ligation would relate to the partial diastereoselectivity of chlorophyll self-assembly and, in particular, the very high diastereoselectivity of the ligation of chlorophylls in photosynthetic proteins.