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J Mazerski

Publications and source records attributed to J Mazerski.

At least 19 recordsLinked to original sources
PubMed2001

MFAME, N-methyl-N-D-fructosyl amphotericin B methyl ester, a new amphotericin B derivative of low toxicity: relationship between self-association and effects on red blood cells.

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.

Amphotericin B↗
PubMed2000

The role of side chains in the interaction of new antitumor pyrimidoacridinetriones with DNA: molecular dynamics simulations.

Pyrimidoacridinetriones (PATs) are a new group of highly active antitumor compounds. It seems reasonable to assume that, like for some other acridine derivatives, intercalation into DNA is a necessary, however not a sufficient condition for antitumor activity of these compounds. Rational design of new compounds of this chemotype requires knowledge about the structure of the intercalation complex, as well as about interactions responsible for its stability. Computer simulation techniques such as molecular dynamics (MD) may provide valuable information about these problems. The results of MD simulations performed for three rationally selected PATs are presented in this paper. The compounds differ in the number and position of side chains. Each of the compounds was simulated in two systems: i) in water, and ii) in the intercalation complex with the dodecamer duplex d(GCGCGCGCGCGC)2. The orientation of the side chain in relation to the ring system is determined by the position of its attachment. Orientation of the ring system inside the intercalation cavity depends on the number and position of side chain(s). The conformations of the side chain(s) of all PATs studied in the intercalation complex were found to be very similar to those observed in water.

Acridines↗
PubMed2000

The intercalation of imidazoacridinones into DNA induces conformational changes in their side chain.

Imidazoacridinones (IAs) are a new group of highly active antitumor compounds. The intercalation of the IA molecule into DNA is the preliminary step in the mode of action of these compounds. There are no experimental data about the structure of an intercalation complex formed by imidazoacridinones. Therefore the design of new potentially better compounds of this group should employ the molecular modelling techniques. The results of molecular dynamics simulations performed for four IA analogues are presented. Each of the compounds was studied in two systems: i) in water, and ii) in the intercalation complex with dodecamer duplex d(GCGCGCGCGCGC)2. Significant differences in the conformation of the side chain in the two environments were observed for all studied IAs. These changes were induced by electrostatic as well as van der Waals interactions between the intercalator and DNA. Moreover, the results showed that the geometry of the intercalation complex depends on: i) the chemical constitution of the side chain, and ii) the substituent in position 8 of the ring system.

Acridines↗
PubMed2000

N-Methyl-N-D-fructosyl amphotericin B methyl ester (MF-AME), a novel antifungal agent of low toxicity: monomer/micelle control over selective toxicity.

Rational chemical modification of amphotericin B (AMB) led to the synthesis of sterically hindered AMB derivatives. The selected optimal compound, N-methyl-N-D-fructosyl amphotericin B methyl ester (MF-AME) retains the broad spectrum of antifungal activity of the parent antibiotic, and exhibits a two orders of magnitude lower toxicity in vivo and in vitro against mammalian cells. Comparative studies of MF-AME and AMB comprising the determination of the spectroscopic properties of monomeric and self-associated forms of the antibiotics, the investigation of the influence of self-association on toxicity to human red blood cells, and of the antibiotic-sterol interaction were performed. On the basis of the results obtained it can be assumed that the improvement of the selective toxicity of MF-AME could in part be a consequence of the diminished concentration of water soluble oligomers in aqueous medium, and the better ability to differentiate between cholesterol and ergosterol.

Amphotericin B↗
PubMed1998

The geometry of intercalation complex of antitumor mitoxantrone and ametantrone with DNA: molecular dynamics simulations.

Intercalative binding of the antitumor drugs ametantrone and mitoxantrone to the dodecamer duplex d(CGCGAGCTCGCG)2 was studied by applying molecular dynamics in water with the GROMOS 87 force field. A number of reasonable binding orientations were tested by short pre-simulations. It was shown that in energetically favourable orientation the anthraquinone chromophore is perpendicular to the direction of inter-base hydrogen bonds. Helically shaped side-chains of the drugs fit to the minor groove. The best orientation obtained in pre-simulations was applied in the main simulations. Small but significant differences were found between structures of intercalation complexes of the two drugs with the dodecamer duplex, the mitoxantrone complex possessing more favourable energy. The molecular nature of interactions responsible for those differences has been discussed.

Antineoplastic Agents↗
PubMed1997

1-[(omega-aminoalkyl)amino]-4-[N-(omega-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines as intercalating cytotoxic agents: synthesis, DNA binding, and biological evaluation.

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.

Acridines↗
PubMed1996

Molecular dynamics of amphotericin B. II. Dimer in water.

Molecular dynamics simulations were performed for a dimer of the antifungal antibiotic, amphotericin B, in water. In the first step of the work three appropriately selected versions of the dimer structure were taken into consideration. In each version antibiotic molecules were placed antiparallel with polar and ionizable groups outside the hydrophobic core formed by polyene chromophores. During short dynamic simulations versions of the dimer structure were compared in respect of the energy of dimerization. The highest energy was observed for the structure in which polyene chromophores superimposed each other as much as possible and this version was subjected to the main simulation. The analysis of 66 snapshot geometries stored during 33 ps dynamic trajectory allowed us to draw three main conclusions: (i) the relative orientation of the amino-sugar moiety and chromophore as well as conformation of the antibiotic macrolide ring were different in both molecules and could exhibit dynamic changes, (ii) the dimer structure exhibited intrinsic asymmetry which could be responsible for characteristic circular dichroism spectra of the aggregated form of the antibiotic, (iii) relatively high stability of the dimer structure resulted not only from hydrophobic interactions between chromophores but also from hydrogen bonds networks that were observed around polar terminals of antibiotic molecules. Implications of these features of the dimer structure for its susceptibility on the ionic state of carboxyl and/or amino groups are also discussed.

Amphotericin B↗
PubMed1996

Constrained search of conformational hyperspace of inactivators of glucosamine-6-phosphate synthase.

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.

Antifungal Agents↗
PubMed1995

Effect of the modifications of ionizable groups of amphotericin B on its ability to form complexes with sterols in hydroalcoholic media.

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.

Amphotericin B↗
PubMed1995

Molecular dynamics of amphotericin B I. Single molecule in vacuum and water.

Molecular dynamics simulations were performed for an antifungal polyene antibiotic amphotericin B (AMB). A single molecule of the AMB was modeled in vacuum as well as in water. In the latter case it was surrounded by 354 SPC water molecules and a periodic boundary condition was applied. An amino-sugar mycosamine ring was found to be rigid in the conditions studied. The mean orientation of this ring in relation to a macrolide ring was found to be common in both simulations and similar to that observed in a crystal of N-iodoacetyl derivative. A large flexibility of the amino-sugar orientation was observed in vacuum in contrast to water simulation. Several conformers of the macrolide ring were observed in vacuum as well as in water simulation. Interactions which may force these conformational transitions have been proposed. The structuring of the water molecules around polar and ionizable parts of the AMB molecule were analysed. The influence of the dynamic behavior of the AMB on structures of supramolecular complexes containing this antibiotic is discussed.

Journal Article↗
PubMed1992

New criterion of placental barrier maturity.

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.

Chorionic Villi↗
PubMed1991

Mechanism of action of anticandidal dipeptides containing inhibitors of glucosamine-6-phosphate synthase.

The mechanism of anticandidal action of novel synthetic dipeptides containing N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP) residues was shown to be consistent with the "warhead delivery" concept. FMDP dipeptides were shown to be transported into Candida albicans cells by the di-tripeptide permease and subsequently hydrolyzed by intracellular peptidases, especially aminopeptidase. The anticandidal activity of the particular FMDP dipeptide was influenced by the rate of its transport and, to a lower extent, by the intracellular cleavage rate. A high transport rate accompanied by a high cleavage rate resulted in the high anticandidal activity of L-norvalyl-FMDP. The strong growth-inhibitory effect of this compound was the consequence of inhibition of the enzyme glucosamine-6-phosphate synthase by the released FMDP. The action of L-norvalyl-FMDP on exponentially growing C. albicans cells resulted in a sharp decrease of incorporation of 14C label from [14C]glucose into chitin, mannoprotein, and glucan. This effect, as well as the growth-inhibitory effect, was fully reversed by exogenous N-acetyl-D-glucosamine. Glucosamine-6-phosphate synthase was proved to be the only essential target for FMDP dipeptides. Scanning electron microscopy of C. albicans cells treated with L-norvalyl-FMDP revealed highly distorted, wrinkled, and collapsed forms. Cells formed long, bulbous chains, and partial lysis occurred.

Biological Transport↗
PubMed1990

Influence of net charge on the aggregation and solubility behaviour of amphotericin B and its derivatives in aqueous media.

The poor solubility of polyene antibiotics in aqueous media limits their application in the therapy of systemic fungal infections. In the present paper we have demonstrated that the ionic state (net electrical charge) of the antibiotic molecule is an important factor in determining the aggregation and solubility properties of amphotericin B and its derivatives. A multi-step model of polyene self-association in aqueous media has been proposed as an explanation for the fact that some major differences are observed when aggregation is monitored by different techniques.

Amphotericin B↗
PubMed1990

QSAR of acridines. II. Features of nitracrine analogs for high anti-tumor activity and selectivity on mice, searched by PCA and MRA methods.

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.

Aminoacridines↗
PubMed1989

Interaction of filipin with dimyristoylphosphatidylcholine membranes studied by 2H-NMR, circular dichroism, electronic absorption and fluorescence.

Interaction of the pentene antibiotic filipin with dimyristoylphosphatidylcholine (DMPC) membranes has been monitored by 2H-NMR, circular dichroism (CD), electronic absorption and fluorescence in the temperature range 10 degrees to 60 degrees 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 x 10(3) M-1, 15 x 10(3) M-1 and 0.6 x 10(3) M-1 at 15 degrees, 30 degrees and 50 degrees 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 2H-NMR spectra of deuterated DMPC indicate that the drug has a slight disordering effect on the lipid matrix below the temperature, Tc, of the gel-to-fluid phase transition and above Tc + 11 degrees 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Antifungal Agents↗
PubMed1988

Quantitative structure-activity relationships in amphotericin B derivatives.

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.

Amphotericin B↗
PubMed1986

Structural features determining the haemolytic activity of vacidin A derivatives.

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.

Antifungal Agents↗