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E Borowski

Publications and source records attributed to E Borowski.

At least 37 records · Page 2Linked to original sources
PubMed1998

Antihistoplasmal in vitro and in vivo effect of Lys-Nva-FMDP.

The new synthetic antifungal agent, L-Lysyl-L-Norvalyl-FMDP, inhibits growth of the yeast form of Histoplasma capsulatum. The compound is transported into the fungal cells by peptide permeases, cleaved intracellularly to constitutive amino acids, and the released C-terminal amino acid inhibits glucosamine-6-phosphate synthase. Promising antihistoplasmal in vivo activity of the FMDP-peptide was observed in an organ load test in mice.

Animals↗
PubMed1997

Conformational analysis of Amphotericin B.

Within a theoretical approach to the problem of antifungal action of Amphotericin B (AmB), a conformational analysis of the neutral and zwitterionic form of this antibiotic in vacuo was performed by the MM2P and AM1 methods. The analysis was carried out with regard to the mutual orientation of the macrolidic and glycosidic fragments of the molecule, which is defined by the phi and psi steric angles. This orientation defines the overall shape of the molecule and is postulated to be important for the antifungal action of the drug. As a result of the MM2P calculations, phi, psi steric energy and population maps were prepared. Several conformers were found on these maps but only two of them (one each for the zwitterionic and the neutral forms of the antibiotic) were previously observed experimentally for isolated molecules. Our other calculated conformers were not observed experimentally but we propose that they may also appear in the AmB channel structure. The results of our conformational analysis were compared with experimental NMR data (nuclear Overhauser effects between selected hydrogen atoms) obtained previously. New structural information obtained for AmB in the present work will be useful for building a molecular model of AmB-target interactions as well as for designing new derivatives of AmB.

Journal Article↗
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↗
PubMed1996

The direct reduction of cytochrome c by some anthraquinone antitumor compounds.

The ability of various anthraquinone antitumor agents to undergo oxidative metabolism with concomitant cytochrome c reduction has been examined. The reduction of cytochrome c by the compounds had enzymatic character and occurred without the formation of oxygen radicals. We have found that the presence of at least two phenolic groups in ring A of the compounds studied was indispensable for their oxidative metabolism. It is suggested that these groups are essential for the binding to cytochrome c. Furthermore, it has been shown that the existence of hydroxy groups in side chains of these compounds augments their interaction with this hemoprotein. On the basis of the results obtained for a series of analogs of mitoxantrone, we can conclude that the structural factor directly responsible for cytochrome c reduction is the primary or secondary amino group of the side chains.

Anthraquinones↗
PubMed1995

Identification of the structural elements of amphotericin B and other polyene macrolide antibiotics of the hepteane group influencing the ionic selectivity of the permeability pathways formed in the red cell membrane.

The selectivity of the transmembrane permeability induced by polyene antibiotics was studied in human erythrocytes and related to the hemolytic potency of the drugs. The selectivity induced was differently, dependent on the antibiotic structure in aromatic (vacidin A, gedamycin) and nonaromatic heptaenes (amphotericin B, candidin). Aromatic heptaenes were more effective than nonaromatic in inducing permeability to K+. For both groups of antibiotics, permeability to K+ was not affected by substitution at the carboxyl group but important differences in the induction of permeability to H+, OH- and Cl- were found. The strongly hemolytic aromatic heptaenes vacidin A and gedamycin exhibited much higher protonophoric activity than the nonaromatic ones: amphotericin B, and candidin. The protonophoric properties of aromatic heptaenes were related to the presence of a free carboxyl group in the antibiotic molecule. Indeed the esterification or amidation of the carboxyl group of vacidin A or gedamycin eliminated the ability of the antibiotic to increase H+ conductance and consequently diminished their hemolytic activity to an important extent. Both groups of antibiotics differed also in the efficiency of anion permeability induction. Only unsubstituted aromatic heptaenes, at high concentration, induced Cl-/OH- exchange and conductive flux of Cl- in a concentration-dependent manner. Substitution at the carboxyl group of vacidin A or gedamycin eliminated this property. Amphotericin B as well as its carboxyl-substituted derivatives formed a pathway characterized by low K+ over Cl- selectivity, whatever the concentration. The hemolytic activity, related to K+ permeability increased by heptaenes was dependent on simultaneous increase of the permeability to anions, and net KCl influx. Carboxyl-substituted derivatives of aromatic heptaenes presenting a remarkably high selectivity for K+, had consequently a very poor hemolytic activity.

Amphotericin B↗
PubMed1995

Synthesis of (dialkylamino)alkyl-disubstituted pyrimido[5,6,1- de]acridines, a novel group of anticancer agents active on a multidrug resistant cell line.

A series of pyrimidoacridine derivatives with two basic side chains, 7a-e, was synthesized, as potential antitumor drugs, starting from 2-[2-(dimethylamino)ethyl]-6-chloropyrimido[5,6,1-de]acridine-1,3, 7- trione (6) and a suitable (alkylamino)alkylamine. The products 6 and 7a-e showed significant cytotoxic activity in vitro against L1210 leukemia. Compounds 7a,d were 2 orders of magnitude more cytotoxic than ametantrone. All compounds were also examined for their activity on LoVo and resistant LoVo/Dx cell lines. Unlike ametantrone, the compounds have shown to be able to overcome the multidrug resistance. Compounds 7a,d, the two most active in vitro, were tested in vivo against murine P388 leukemia showing good activity.

Acridines↗
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↗
PubMed1995

Amide and ester derivatives of N3-trans-epoxysuccinoyl-L-2,3-diaminopropanoic acid: inhibitors of glucosamine-6-phosphate synthase.

Several analogs 5, 6, 7, 8, 10 and 11 of the C-terminal fragment of a peptide antibiotic Sch 37137 were designed and tested as inhibitors of glucosamine-6-phosphate synthase from Saccharomyces cerevisiae. From IC50 values and kinetic parameters of inhibition of glucosamine-6-phosphate synthase by compounds 5-11 it has been found that the inhibitory potency of these compounds follows the order: 6 > 5 > 8 > 9 > 7, 10, 11. This suggests that an inhibitor with a primary amido group binds better to the active site of the enzyme than other inhibitors. The order of reactivity of compounds 5-11 may be attributed to a steric inability of the inhibitor to fit into the active site of the enzyme and also indicates the importance of the chirality of trans-epoxysuccinic acid on the inhibitory properties of the synthesized compounds.

Amides↗
PubMed1995

Stereostructure of perimycin A.

The gross structure of perimycin A was revised: the position of the keto group was changed from C-13 to C-5. The stereostructure of perimycin A was established based upon NMR studies.

Acetophenones↗
PubMed1995

Stereostructure of Rimocidin.

NMR studies of rimocidin, consisting of DQF-COSY, ROESY, HSQC, HMBC and 1D-TOCSY experiments, resulted in the assignment of the absolute configuration of the rimocidin chiral centers as 2S, 3R, 9S, 11R, 13S, 14R, 15S, 17R, and 27R. The geometry of tetraene chromophore was found to be all-trans.

Antifungal Agents↗
PubMed1995

Molecular modeling of singlet-oxygen binding to anthraquinones in relation to the peroxidating activity of antitumor anthraquinone drugs.

Anthraquinone derivatives are important anti-cancer drugs possessing, however, undesirable peroxidating and, in consequence, cardiotoxic properties. This results from the mediation by these compounds of the one-electron reduction processes of the oxygen molecule, which produces the highly toxic superoxide anion radical and other active oxygen species. This article summarizes the results of our studies on the molecular aspects of the mechanism of anthraquinone-mediated peroxidation which were carried out using enzymatic-assay, electrochemical, and quantum-mechanical methods.

Anthraquinones↗
PubMed1994

The role of amphotericin B amino group basicity in its antifungal action. A theoretical approach.

The role of basicity of the amine group of amphotericin B in the molecular mechanism of antifungal activity of this antibiotic has been investigated by AM1 and MNDO quantum chemistry methods. Calculations of proton affinity of the amine group, as a measure of its basicity, for appropriate models of free amphotericin B and its N-alkyl derivatives were carried out. These studies were preceded by a critical examination of the usefulness and reliability of both methods to predict the proton affinities of several aliphatic amines. It has been concluded that the diminution of protonability of the substituted amine group of amphotericin B correlates with the decrease of antifungal activity of the appropriate derivatives of antibiotic. It was experimentally demonstrated (A. Czerwiński et al., J. Antibiot. 44 (1991) 979) that the introduction of additional amine groups in such a derivative restores antifungal activity of the compound. In our studies it was evidenced, using theoretical methods, that the proton affinity of this additional amine group is similar to that in free amphotericin B.

Amines↗
PubMed1994

Synthesis and anticandidal activities of optimized analogs of antibiotic Sch 37137.

Peptide analogues of Sch 37137 the antifungal antibiotic have been synthesized and evaluated in vitro against Candida sp. Di- and tripeptides containing methionine, leucine, norvaline, lysine, glutamic acid and N3-(trans-epoxysuccinamoyl)-L-2,3-diaminopropanoic acid, (EADP) were obtained. Peptides containing (D)-, and (L)-trans-epoxysuccinamic acid were also prepared. All of the analogues examined displayed in general higher anticandidal activity than a mixture of diastereomers of Sch 37137.

Amino Acids, Diamino↗
PubMed1994

Specific inhibition of acid proteinase secretion in Candida albicans by Lys-Nva-FMDP.

Secretion of aspartic (acid) proteinase by Candida albicans is inhibited by the action of a new anticandidal agent, L-lysyl-L-norvalyl-[N3-(4-methoxyfumaroyl)]-L-2,3-diamino pro panoic acid (Lys-Nva-FMDP), at low, even sub-minimum inhibitory concentrations. The observed phenomenon is a direct consequence of inhibition of the enzyme, glucosamine-6-phosphate synthase. As a result of this inhibition, biosynthesis of candidal mannoproteins is markedly reduced. A possible correlation between general inhibition of mannoprotein biosynthesis and acid proteinase secretion is suggested. The reported inhibition of acid proteinase secretion by Lys-Nva-FMDP is more specific than the previously described effects of methyl patricin, 5-fluorocytosine and fenticonazole.

Aspartic Acid Endopeptidases↗