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Two-dimensional variance analysis of the results of determination of NO3, SO42, F, Al3+, C1, NH4+, PO&sup3-;[sub4], Fe&sup3+;, Ca&sup2+;, K[sup+] and Mg&sup2+;, and d and electrolytic conductivity of precipitation water samples collected in the Tricity area showed that transregional transport of pollutants affects air quality in this region. Over the large area of the Tricity agglomeration fluctuations in analyte concentrations in precipitation water samples are not affected on a statistically significant level by localizing sampling sites, but the area affected by transport direction of air mass movement. [ABSTRACT FROM AUTHOR]

Interaction of the pentene antibiotic filipin with dimyristoylphosphatidylcholine (DMPC) membranes has been monitored by H-NMR, circular dichroism (CD), electronic absorption and fluorescence in the temperature range 10° to 60°C. Interaction appears to depend on whether filipin is added before or after membrane formation and also upon the temperature of the system. When filipin is added to preformed DMPC large unilamellar vesicles (LUV), the association constants, as determined by electronic absorption are 39×10 M, 15×10 M and 0.6×10 M at 15°, 30° and 50°C, respectively. Under identical conditions, CD spectra of bound filipin exhibit features characteristic of an aggregation over the whole temperature range. When filipin is incorporated in membranes during their preparation, the H-NMR spectra of deuterated DMPC indicate that the drug has a slight disordering effect on the lipid matrix below the temperature, T,of the gel-to-fluid phase transition and above T+11°C. Between these two temperature boundaries the system consists of two lipid regions of very different dynamic properties. One of the regions, which is attributed to a filipin-lipid complex, has the properties of gel-like lipids whereas the other has those of fluid-like lipids. The latter domain is however more ordered than the pure lipid at corresponding temperatures. CD spectra under the same conditions are found to be identical to spectra when the drug is added to preformed membranes, only in the region Tto T+11°C. Filipin induced carboxyfluorescein release from DMPC-LUV is found to be complete when the filipin-to-lipid ratio is near 1, for temperatures below T+11°C. Results are compared to previous data on amphotericin B and provide evidence that the gel-like structure of phospholipid and membrane permeation may be induced by filipin even in the absence of cholesterol. [ABSTRACT FROM AUTHOR]

Triazoloacridinone C-1305, a potent antitumor agent recommended for Phase I clinical trials, exhibits high activity towards a wide range of experimental colon carcinomas, in many cases associated with complete tumor regression. C-1305 is a well-established dsDNA intercalator, yet no information on its mode of binding into DNA is available to date. Herein, we present the NMR-driven and MD-refined reconstruction of the 3D structures of the d(CGATATCG) 2 :C-1305 and d(CCCTAGGG) 2 :C-1305 non-covalent adducts. In both cases, the ligand intercalates at the TA/TA site, forming well-defined dsDNA:drug 1:1 mol/mol complexes. Orientation of the ligand within the binding site was unambiguously established by the DNA/ligand proton-proton NOE contacts. A subsequent, NMR-driven study of the sequence-specificity of C-1305 using a series of DNA duplexes, allowed us to confirm a strong preference towards TA/TA dinucleotide steps, followed by the TG/CA steps. Interestingly, no interaction at all was observed with duplexes containing exclusively the AT/AT, GG/CC and GA/TC steps.

Environmental pollution, for example with metals, can significantly affect the ecosystem balance leading to severe changes. Biologically active pigments are relevant for the appearance and condition of birds. Melanin and carotenoid particles are the most frequently deposited pigments in avian integument. They are responsible for the majority of colors of bird plumage. The phenotypic expression can be affected by metal contamination. It can be manifested as color bleaching or differences in the size of plumage badges. In this study, we performed a comprehensive review of related studies in order to estimate the underlying population effect of this potential dependency. The study is based on the review of the literature regarding several avian species. It was designed to identify an area where the effect of the exposure is still poorly known. The analysis was specifically conducted to investigate the correlation between trace element concentration and eumelanin deposition. Moreover, we searched for factors that could affect spectral properties of feathers with carotenoid-based pigmentation. As a result, we found carotenoid-based pigmentation to be of a good use in terms of visual condition assessment. Changes in melanin-based pattern should be analyzed separately for eu- and pheomelanin as well as for a range of essential and toxic elements. Comprehensive studies on the subject are still scarce. Therefore, the issue requires further investigation.

Over the years, noticeable effort has been directed towards contaminant determination in multiple biotic samples collected from the inhabitants of the Arctic. Little consideration has been given to polar herbivores, however, especially those from the European parts of the Arctic. To provide a broader perspective, we aimed to decipher trace element concentration in hairs of the key species in the Arctic, namely the Svalbard reindeer (Rangifer tarandus platyrhynchus), and to recognise whether diet variations could correspond with forward exposure. The effect of habitat and diet was investigated using the ratios of stable isotopes of carbon (δ 13 C) and nitrogen (δ 15 N), and previous literature studies on vegetation from the areas of interest. Analysis was performed for eighteen elements in total, both toxic and essential. Metals were present in a decreasing order Fe > Zn > Ba > Cu > Pb > Cr > Ni > V > Ga =La > Rb > As > Li > Co > Hg > Cd > Cs > Be. Similarity in trends in the studied subpopulations was observed for many metals. A significant log-linear correlation was observed for most of the elements, excluding nitrogen and carbon isotopes signature. Extremely high iron levels were determined in some of the samples, suggesting past iron overload. Zinc, in contrast to the remaining metals, did not correlate well with any other element. Mercury was determined at very low levels, in accordance with previous literature regarding its concentrations in moss and lichen species in Svalbard. The analysis of stable isotopes showed a high variation in nitrogen isotopes signatures. Further research is required to properly evaluate the potential health risks and ecological implications of elevated exposure., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Imidazoacridinone C-1311 (Symadex®) is a powerful antitumor agent, which successfully made its way through the Phase I clinical trials and has been recommended for Phase II few a years ago. It has been shown experimentally that during the initial stage of its action C-1311 forms a relatively stable intercalation complex with DNA, yet it has shown no base-sequence specificity while binding to DNA. In this paper, the d(CGATCG)2:C-1311 intercalation complex has been studied by means of two-dimensional NMR spectroscopy, yielding a full assignment of the resonance lines observed in (1)H NMR spectra. The observation of the intermolecular NOE contacts between C-1311 and DNA allowed locating the ligand between the guanine and adenine moieties. Formation of a symmetric complex was pointed out on the basis of the lack of a second set of the (1)H resonances. The resulting stereostructure of the complex was then improved by means of molecular dynamics, using the CHARMM force field and GROMACS software. To this end, distance restraints derived from the NOESY cross-peak volumes were applied to the atomistic model of the d(CGATCG)2:C-1311 complex. Obtained results are in full agreement with biochemical data on the mechanism of action of C-1311, in particular with the previously postulated post-intercalation enzymatic activation of the studied drug.

Acridines belong to a group of polycyclic heteroaromatic compounds and exhibit a broad spectrum of biological activity including antiprotozoal, antibacterial, antiviral and antitumor activity. Acridine derivatives with antitumor activity have different mechanisms of action at the molecular level. The data obtained so far indicate that one of the main steps is the formation of physico-chemical complexes with DNA. Among acridine derivatives with anticancer activity we can distinguish five main classes of compounds: nitroacridines, 9-anilinoacridines, pyrazoloacridines, imidazoacridines, and triazoloacridines. Compounds from different classes differ both in mechanism of action and spectrum of antitumor activity.

DNA is a molecular target for many anticancer and antiviral drugs. Therefore, a clear understanding of the interaction of small molecules with DNA is important in the rational design of ligands that can bind to DNA with high affinity and selectivity. There are several methods to investigate interactions between drug and DNA. Some of them measures changing into DNA structures, such as lengthening and untwisting of helix of DNA. Other techniques measure changing in drug environment. With the increasing availability of sensitive microcalorimeters, particular interest has arisen in the thermodynamics of drug-DNA interaction. Using such methods permit direct determination of enthalpy changes associated with reactions. One experiment permits to obtain also binding constant, hence an almost complete thermodynamic profile can be established. This profile offers key insights into the molecular forces that drive complex formation and permit to estimate which kind of interaction are responsible of forming these complexes.

The work presented is a part of our continual study on the behavior of the polyene macrolide antibiotic amphotericin B (AmB) complexes with sterols on the molecular level. In contrast to the previously researched AmB-ergosterol binary complex, the AmB-ergosterol-AmB aggregates simulated of 2:1 stoichiometry retain significantly higher stability and relatively rigid, "sandwich" geometry. Van der Waals forces with a considerable share of the electrostatic interactions are responsible for such behavior. System of the intermolecular hydrogen bonds also seems to be of notable importance for the complex's structure preservation. The most energetically favored geometries match fairly close the geometric criteria and the network of interactions postulated in the contemporary hypothetical and computational models of antibiotic-sterol complexes. On the basis of works previously published and the present study novel hypotheses on the AmB selectivity towards sterols varying in chemical structure and on the possible mechanisms of channel structure formation were presented.

Levels of seven marker polychlorinated biphenyls (PCBs) have been determined in five species of Baltic fish collected during 1997-2006. Downward time trends in the concentrations of heavier congeners of PCBs in different Baltic fish, with the exception of cod, have been observed between 1997 and 2001. In case of sprat and herring samples, the statistical significance of the time trends of the PCBs: 101, 118, 153, 138 and 180 concentrations has been proved. Species-specific bioaccumulation of PCBs has been indicated, and the lowest and highest levels of PCBs (expressed on the basis of lipid weight) have been observed in sprat and salmon samples, respectively. PCB profiles have been found to be similar in all the fish species tested. Sampling location has not been a crucial factor for the observed levels of various PCBs. In some fish species, PCB concentrations are negatively correlated with the fat content but have no relation with the fish length.

The levels of HCH isomers, HCB and summation DDTs were determined in five species of Baltic fish collected during 1995-2006. Some downward time trends of HCH isomer, pp'-DDE and pp'-DDD concentrations in Baltic fish were observed; in contrast, HCB and DDT concentrations did not exhibit any obvious trend. Concentrations of summation HCHs expressed on a lipid weight basis were very similar in all species studied. In contrast, concentrations of summation DDTs varied in tested species. The most abundant HCH isomer was beta-HCH and among DDT-related compounds, pp'-DDE prevailed. In our investigations the sampling sites were not a crucial factor for organochlorine pesticide concentrations and patterns observed in fish, but the occurrence of several inter-species differences in the bioaccumulation features of OC pesticides were observed. For cod there was a positive correlation between fish size (length) and summation DDT concentration. In herring, sprat and salmon samples, summation DDT concentrations were negatively correlated with fat content.

Synthetic antitumor anthracenedione drugs, in contrast to anthracycline antibiotics, are ineffective in free radical formation in NADH dehydrogenase system. Our results have indicated that neither the reduction potential nor the side chain conformation and the energies of border orbitals (HOMO and LUMO) determine the ability of anthracenediones to stimulate reactive oxygen species formation in NADH dehydrogenase system. It was shown that the distribution of the molecular electrostatic potential (MEP), around the quinone system was crucial for this ability. We have found for non-stimulating anthracenediones that the clouds of positive MEP cover the quinone carbon atoms while for agents effective in stimulating reactive oxygen species formation the clouds of negative MEP cover continuously the aromatic core together with the quinone system.

Fungal infections are a growing problem in contemporary medicine, yet only a few antifungal agents are used in clinical practice. In our laboratory we proposed the enzyme L-glutamine: D-fructose-6-phosphate amidotransferase (EC 2.6.1.16) as a new target for antifungals. The structure of this enzyme consists of two domains, N-terminal and C-terminal ones, catalysing glutamine hydrolysis and sugar-phosphate isomerisation, respectively. In our laboratory a series of potent selective inhibitors of GlcN-6-P synthase have been designed and synthesised. One group of these compounds, including the most studied N3-(4-methoxyfumaroyl)-l-2,3-diaminopropanoic acid (FMDP), behave like glutamine analogs acting as active-site-directed inactivators, blocking the N-terminal, glutamine-binding domain of the enzyme. The second group of GlcN-6-P synthase inhibitors mimic the transition state of the reaction taking place in the C-terminal sugar isomerising domain. Surprisingly, in spite of the fact that glutamine is the source of nitrogen for a number of enzymes it turned out that the glutamine analogue FMDP and its derivatives are selective against GlcN-6-P synthase and they do not block other enzymes, even belonging to the same family of glutamine amidotransferases. Our molecular modelling studies of this phenomenon revealed that even within the family of related enzymes substantial differences may exist in the geometry of the active site. In the case of the glutamine amidotransferase family the glutamine binding site of GlcN-6-P synthase fits a different region of the glutamine conformational space than other amidotransferases. Detailed analysis of the interaction pattern for the best known, so far, inhibitor of the sugar isomerising domain, namely 2-amino-2-deoxy-D-glucitol-6-phosphate (ADGP), allowed us to suggest changes in the structure of the inhibitor that should improve the interaction pattern. The novel ligand was designed and synthesised. Biological experiments confirmed our predictions. The new compound named ADMP is a much better inhibitor of glucosamine-6-phosphate synthase than ADGP.

The novel group of amphotericin B (AmB) cationic derivatives has been examined in terms of relationship between self-association and selective toxicity. In all determinations AmB has been used as reference compound. In vitro toxic effects of the compounds on human erythrocytes were determined by measuring leakage of intracellular potassium ions and hemolysis. Antifungal effects were determined as MIC and intracellular potassium loss. The compounds self-association was followed by UV-Vis spectroscopy. The results suggested that: i) unlike AmB the monomer/self-associated species ratio is not an essential in governing the selective toxicity of the derivatives studied; ii) the presence of a bulky substituent in the AmB molecule, preferably located at the amino group of mycosamine moiety is the structural factor essential for the selective toxicity improvement.

Membrane located sterols determine the structure and function of eucariotic cell membranes. Moreover, they are targets for important antifungal antibiotic amphotericin B. Knowledge about the geometry and dynamics of sterols in the environment of lipidic membranes is necessary to understand their functions. However, due to the dynamic character of the membrane, no experimental data about sterol behaviour on the molecular level is available. Hence molecular modelling simulations could be a source of useful information. The main goal of this paper is to prove the adequacy of the GROMOS 96 force field for molecular simulations of membrane sterols. We focused our attention on the reproduction of characteristic geometrical features observed in the crystal of cholesterol hemiethanolate by molecular dynamics simulations. The results presented clearly indicate that the GROMOS 96 force field can be a useful tool to simulate the highly lipophilic systems. Moreover, interactions responsible for the stability of such systems can also be recognised.

The properties of amphotericin B-ergosterol primary complex have been studied with the use of the molecular dynamics simulation. Possible geometries of the complex were tested first in order to find the structures with the most favourable values of the intermolecular interactions energy. The molecules studied possessed a tendency to fit each other's shapes, which favours intermolecular van der Waals interactions. The main simulations were performed for the best structures found. Presence of hydrogen bonds between the sterol hydroxyl group and polar fragments of mycosamine (most frequently 2'OH) was coupled with a relatively high level of the intermolecular energy values. The structures obtained are hardly comparable to the hypothetical and 'computational' models of the antibiotic-sterol complex. The geometries found are not suitable to assemble the presupposed structure of the water channel, however, the existence of the complex in the shape anticipated is not in contradiction to the results of biophysical experiments on the complexation in water and in hydroalcoholic media.

In aqueous solutions N-methyl-N-D-fructosyl amphotericin B methyl ester (MFAME), a novel amphotericin B derivative with low animal toxicity, similar to its parent antibiotic, exists in three forms: monomeric, soluble and insoluble aggregates in equilibrium [1]. The aim of our work was to examine the influence of medium composition on the MFAME self-association and the relationship between MFAME self-association and its toxicity towards red blood cells. The toxicity of MFAME in aggregated state towards red blood cells was tested by measuring the induction of potassium leakage and extent of haemolysis. The proportions of antibiotic species present in various aqueous media were determined by analysis of the UV-Vis spectra as a function of the antibiotic concentration. Numeric decomposition of the spectra allowed identification of four spectral species present in MFAME solutions: monomeric and three aggregated forms. Our results indicate that these aggregates, named type I, type II and type III, are different in terms of spectral properties, as well as effectiveness towards red blood cells. Soluble aggregate types I and III are the active forms of MFAME towards erythrocytes. The medium composition seems to be the main factor determining which type of antibiotic aggregate prevails in solution.

A series of DNA-intercalating potential antitumor agents, 1-[(omega-aminoalkyl)amino]-4-[N-(omega-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines, has been prepared by aminolysis of the corresponding 4-[N-(omega-aminoalkyl)carbamoyl]-1-chloro derivative with a suitable omega-aminoalkylamine. The noncovalent DNA-binding properties of these bis-functionalized compounds have been examined using a combination of fluorometric and thermal denaturation techniques and are compared with the behaviors for established DNA intercalants and cationic minor groove ligands. The results indicate that (i) the agents are considerably more DNA-affinic than less functionalized acridinones, with 'apparent' binding constants of (0.1-2.1) x 10(7) and (0.3-7.5) x 10(7) M-1 at pH 5 and 7, respectively, (ii) overall affinity is sensitive to both the length of the flexible side chain and the complexity of the attached amine substituents, and (iii) the pendant side chains effect a switch to moderate AT-preferential binding. In vitro cytotoxic potencies toward six tumor cell lines broadly parallel the observed DNA affinities, although poor correlation is evident for certain compounds. The octanol/water partition coefficients have been also calculated, but there is no correlation with cytotoxicity values. Two highly DNA-affinic analogs, 10 and 13, have been identified with a useful broad spectrum of cytotoxic activity.

Glucosamine-6-phosphate (GlcN-6-P) synthase (EC 2.6.1.16) is a key enzyme in amino sugar metabolism in micro-organisms and its selective and irreversible inhibitors can become valuable antifungal drugs. We performed a constrained search of the conformational hyperspace of glutamine and of the set of specific inactivators of the enzyme, as well as of some non-specific inhibitors of many cysteine containing enzymes. From these calculations we obtained spatial relationships of functional groups, the presence and specific orientation of which in the active site of the enzyme is important for effective and selective action of the inhibitor. Subsequent quantum chemical calculations confirmed the correctness of the pharmacophore conformation we obtained. Pharmacophore conformation of FMDP molecule, the most potent inhibitor in the selective inhibitors group, is placed close to the energy minimum on the conformational energy map.

The interaction of amphotericin B and some of its semisynthetic derivatives with cholesterol and ergosterol has been tested in 1:4 (v/v) ethanol/water mixture by circular dichroism and absorption spectroscopy. The effect of the chemical modification of the 'ionizable head' of the antibiotic, the pH of the medium, and the sterol/antibiotic ratio has been studied. The results obtained show that in the presence of the sterols, amphotericin B forms several spectroscopically different species. A high extent of polyene-sterol interaction is observed for: (i) amphotericin B in neutral or acidic media, (ii) esters and amides at neutral or alkaline media, (iii) N-acyl derivatives only in acidic medium. The extent of interaction at neutral pH is highly correlated with the biological activity of compounds tested. The implication of these findings on the nature of the forces responsible for the antibiotic-sterol interaction is discussed.

In 120 full term pregnancies and 20 premature deliveries number of plates thickness of epithelial plate and number of vili in 1 mm2 placenta have been determined by histological investigation. These morphometric studies lead to the following conclusion: the increase of placental transport ability corresponds with fetal age and weight. The ratio between number of plates to their thickness is introduced as transportation index. There is a correlation between placental morphology and fetal maturity.

Synthesis and biological properties of amphotericin B O-methyl oxime are described. The presence of an intact hemiketal ring in the antibiotic molecule appeared to be essential for its biological activity.

A study of quantitative structure-activity relationships (QSAR) of 32 nitro-9-aminoacridine derivatives has been carried out. The results of the four biological tests in vitro, anti-tumor activity against S-180 and toxicity on healthy as well as on tumor bearing mice were subjected to principal component analysis (PCA). Two significant principal components PC1 and PC2 (containing 81.4% and 8.1% of total data set information, respectively) were extracted. The biological meaning of PCs was identified: PC1 corresponds to a general biological activity, PC2 mainly to selectivity. To obtain predictability of biological activities multiple regression analysis (MRA) for PC1 and PC2 were used. The general biological activity (PC1) is parabolically dependent on the lipophilicity (log P*) of the substituent on 9-amino group (R = 0.97); selectivity (PC2), however, on the shape index 2K and the indicator variable IN2N (R = 0.76). For high antitumor activity and improved therapeutic effectivity (LD50/ED50) 1-nitro-9-amino-acridines should be characterized by: (i) lipophilicity, expressed as log P*, between -1 and -2; (ii) three or more methylene spacers between proximal and distal nitrogen atoms in the side chain, if the distal nitrogen is present; (iii) high 2K value for the side chain, as for a large and preferably unbranched substituent on C9.

The interactions of unilamellar lipid vesicles with vacidin A, an aromatic heptaene antibiotic, and with amphotericin B, a nonaromatic heptaene antibiotic were compared. Uptake of both antibiotics, monitored by circular dichroism, was found to be faster with small vesicles than with large ones. By combining permeability measurements (Gary-Bobo and Cybulska, J. Antibiotics 35, 1068 (1982)) and circular dichroism spectra, we found that for vacidin A, the same permeability inducing species is formed regardless of vesicles size. However, at a given concentration of antibiotic, less of the permeability inducing species is formed in the presence of small vesicles than in the presence of large vesicles. This may account for the differences between small and large vesicles in antibiotics-induced permeability. For amphotericin B, the permeability inducing species formed in the presence of small vesicles differs from that formed in the presence of large vesicles.

The haemolytic activity of aromatic heptaene antifungal antibiotics (vacidin A and its analogues) can be decreased by chemical modification. It has been shown that the ionic state of the polar head of the antibiotic molecule is essential for this activity. The effect of the net charge of the antibiotic molecule on association constant, K, between polyene and membrane-located cholesterol; and the number, n, of antibiotic molecules per one erythrocyte critical for lysis induction was investigated. In addition, changes in the structure of the polyene-cholesterol complex were monitored by circular dichroism spectroscopy. Zwitterionic native antibiotics (vacidin A and gedamycin), the negatively charged N'-acetyl derivatives and the positively charged methyl esters were used in these studies. The results presented indicate that two different phenomena are responsible for the decrease in the haemolytic activity of the compounds studied: for N'-acetyl derivatives the decrease of activity is mainly a result of lower affinity of negatively charged molecules to the membranes; for methyl esters the drastic decrease of activity is mainly a result of the different structure of the antibiotic-cholesterol complex. The permeabilizing species formed from these complexes are characterized by very low efficiency of ion permeation.

The quantitative structure-activity relationships studies of amphotericin B and its 16 semisynthetic derivatives obtained by modification at carboxyl and amino groups have been done. The results of five biological tests were subjected to principal component analysis, a numerical method useful in the investigation of large sets of data. For some compounds, also, interaction with lipidic vesicles was investigated by spectroscopic methods. The results obtained indicate that: (i) The presence of positively charged nitrogen atom (protonable or bearing fixed charge) is indispensable for biological activity and antibiotic-sterol interaction; (ii) The lack of free carboxyl group in the molecule favours the differentiation between cholesterol and ergosterol containing cells.