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1
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The ability to overcome multidrug resistance of tumor cell lines by novel acridine cytostatics with condensed heterocyclic rings.

100%
Bontemps-Gracz M. M., Kupiec A., Antonini I., Borowski E.
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2002
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vol. 49
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issue 1
87-92
EN
Two recently synthesized groups of acridine cytostatics containing fused heterocyclic ring(s): pyrazoloacridines (PAC) and pyrazolopyrimidoacridines (PPAC) were tested in regard to their in vitro cytotoxic activity towards a panel of sensitive and resistant human tumor cell lines. The obtained results corroborate our earlier hypothesis on the essential role of heterocyclic ring fused to the acridine moiety in the ability of acridine cytostatics to overcome multidrug resistance of tumor cells. The presence, location and kind of substituents considerably influenced both the cytotoxic activity of the derivatives and their ability to overcome multidrug resistance. The same factors also affected the cytostatics ability to differentiate between tumor cell lines with various types of drug exporting pumps.
2
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Molecular modelling of membrane activity of amphotericin B, a polyene macrolide antifungal antibiotic

100%
Baginski M., Sternal K., Czub J., Borowski E.
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2005
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vol. 52
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issue 3
655-658
EN
Amphotericin B (AmB) is a well known polyene macrolide antibiotic used to treat systemic fungal infections. Despite its toxicity AmB is still regarded as a life-saving drug. The lack of adequate knowledge of the AmB mechanism of action is a serious obstacle to efficient development of new less toxic derivatives. Complementary to various experimental approaches, computational chemistry methods were used to study AmB mechanism of action. A programme lasting for a decade, that was run by our group covered studies of: i) molecular properties of AmB and its membrane targets, ii) structure and properties of AmB membrane channels, and iii) interaction of AmB with the membrane.
3
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Comparative in vitro studies on liposomal formulations of amphotericin B and its derivative, N-methyl-N-D-fructosyl amphotericin B methyl ester (MFAME).

100%
Cybulska B., Kupczyk K., Szlinder-Richter J., Borowski E.
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2002
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vol. 49
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issue 1
67-75
EN
N-Methyl-N-D-fructosyl amphotericin B methyl ester (MFAME) is a semisynthetic derivative of the antifungal antibiotic amphotericin B (AMB). In contrast to the parent antibiotic, the derivative is characterised by low toxicity to mammalian cells and good solubility in water of its salts. Comparative studies on biological properties of free MFAME, AMB and their liposomal formulations were performed. To obtain liposomal forms, the antibiotics were incorporated into small unilamellar vesicles composed of dimyristoyl phosphatidylcholine (DMPC) and DMPC:cholesterol or ergosterol, 8:2 molar ratio. The effectivity of the liposomal and free forms of AMB and MFAME were compared by determination of fungistatic and fungicidal activity against Candida albicans ATCC 10261, potassium release from erythrocytes, and haemolysis. The results obtained indicate that in contrast to AMB, incorporation of MFAME into liposomes did not further improve its selective toxicity. Studies on the antagonistic effect of ergosterol and cholesterol on the antifungal activity of the antibiotics indicated that sterol interference was definitely less pronounced in the case of MFAME than in the case of AMB.
4
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Glucosamine-6-phosphate synthase, a novel target for antifungal agents. Molecular modelling studies in drug design.

100%
Wojciechowski M., Milewski S., Mazerski J., Borowski E.
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2005
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vol. 52
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issue 3
647-653
EN
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.
5
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Strategies for overcoming ABC-transporters-mediated multidrug resistance (MDR) of tumor cells

100%
Borowski E., Bontemps-Gracz M. M., Piwkowska A.
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2005
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vol. 52
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issue 3
609-627
EN
The development of multidrug resistance (MDR) of tumors is a major cause of failure in antitumor chemotherapy. This type of crossresistance is due to the expression of ABC transporter glycoproteins actively effluxing the drug from the cells against the concentration gradient at the expense of metabolic energy, thus preventing the accumulation in cells of therapeutic concentration of active agents. In this review strategies for overcoming this adverse phenomenon are discussed. They comprise the control of expression of MDR glycoprotein transporters and control of the functioning of the expressed transporter proteins. The latter approach is discussed in more detail, comprising the following general strategies: (i) development of compounds that are not substrates of efflux pump(s), (ii) use of agents that inactivate (inhibit) MDR proteins, (iii) design of cytostatics characterized by fast cellular uptake, surpassing their mediated efflux, (iv) use of compounds competing with the drug for the MDR protein-mediated efflux. Positive and negative aspects of these strategies are analysed, with special attention put on strategy based on the use of MDR modulators in combination therapy, allowing the restoration of cytotoxic activity of clinical cytostatics towards resistant tumor cells.
6
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The influence of L - norvalyl - N^3 - 4 - methoxyfumaroyl - L - 2,3 - diaminopropanoic acid, an antifungal agent, on mammalian cells in tissue culture

100%
Bontemps-Gracz M., Milewski S., Borowski E.
Acta Biochimica Polonica
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1991
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vol. 38
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issue 2
229-239
7
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Low stimulation of NADH oxidation and oxygen consumption by 5-iminodaunorubicin and its derivatives

100%
Tarasiuk J., Stefańska B., Borowski E.
Acta Biochimica Polonica
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1990
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vol. 37
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issue 2
251-259
8
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The geometry of intercalation complex of antitumor mitoxantrone and ametantrone with DNA: Molecular dynamics simulations

100%
Mazerski J., Martelli S., Borowski E.
Acta Biochimica Polonica
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1998
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vol. 45
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issue 1
1-11
9
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Comparative studies on cell stimulatory, permeabilizing and toxic effects induced in sensitive and multidrug resistant fungal strains by amphotericin B (AMB) and N-methyl-N-D-fructosyl amphotericin B methyl ester (MFAME).

88%
Szlinder-Richert J., Cybulska B., Grzybowska J., Borowski E., Prasad R.
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2000
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vol. 47
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issue 1
133-140
EN
N-Methyl-N-D-fructosyl-amphotericin B methyl ester (MFAME) is a new derivative of amphotericin B, which is characterised by low toxicity to mammalian cells and good solubility in water of its salts. The antifungal activity and effects of MFAME towards Candida albicans and Saccharomyces cerevisiae multidrug resistant MDR(+) and sensitive MDR(-) strains was compared with those of parent compound. The results obtained indicate that MDR(+) S. cerevisiae was sensitive to MFAME as well as to AMB. MFAME exhibited the same effects on fungal cells studied as parent antibiotic. The two antibiotics, depending on the dose applied induced cell stimulation, K+ efflux, and/or had a toxic effect.
10
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Facilitated diffusion of glucosamine-6-phosphate synthase inhibitors enhances their antifungal activity.

88%
Janiak A., Cybulska B., Szlinder-Richter J., Borowski E., Milewski S.
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2002
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vol. 49
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issue 1
77-86
EN
N3-(4-Methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP) and 2-amino-2-deoxy-D-glucitol-6-phosphate (ADGP) are strong inhibitors of the essential fungal enzyme, glucosamine-6-phosphate synthase, but their antifungal activity is poor, due to slow penetration of these agents through the cytoplasmic membrane. In the present studies we have exploited the possibility of enhancement of ADGP and FMDP antifungal activity by improving their transport properties. It has been found that membrane-permeabilising polyene macrolides amphotericin B (AMB) and its N-methyl-N-fructosyl methyl ester derivative (MF-AME), at subinhibitory concentrations, facilitate diffusion of ADGP through the fungal cell membrane, thus allowing a decrease of its minimal inhibitory concentration (MIC). Synergistic effects have been observed for combinations of ADGP with AMB or MF-AME. Fractional inhibitory concentration (FIC) indexes, determined against a number of Candida spp., have been in the 0.18-0.81 range. Weak antifungal synergistic effects have been found for combinations of FMDP with AMB or MF-AME. ADGP can be easily encapsulated into unilamellar lipid vesicles. Liposomal preparations of ADGP demonstrated stronger antifungal activity against some fungal strains than free ADGP.
11
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The selectivity of amino acids and peptides amidination with O-methylisourea

87%
Wojciechowska H., Zgoda W., Borowski E.
Acta Biochimica Polonica
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1982
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vol. 29
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issue 3-4
197-204
12
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N-Methyl-N-D-fructosyl amphotericin B methyl ester (MF-AME), a novel antifungal agent of low toxicity: Monomer/micelle control over selective toxicity.

76%
Cybulska B., Gadomska I., Mazerski J., Grzybowska J., Borowski E., Cheron M., Bolard J.
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2000
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vol. 47
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issue 1
121-131
EN
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.
13
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The ability of new formamidine sugar-modified derivatives of daunorubicin to stimulate free radical formation in three enzymatic systems: NADH dehydrogenase, NADPH cytochrome P450 reductase and xanthine oxidase

76%
Pawłowska J., Tarasiuk J., Borowski E., Wąsowska M., Oszczapowicz I., Roland Wolf C.
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2000
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vol. 47
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issue 1
141-147
EN
Some sterically hindered N-substituted derivatives of daunorubicin are known to be poor substrates for NADH dehydrogenase, NADPH cytochrome P450 reductase and xanthine oxidase. In consequence, poor oxygen radical generation by these compounds is observed. In this study we examined a new family of sugar-N-substituted derivatives of daunorubicin bearing a bulky substituent introduced on the nitrogen atom through the amidine spacer. These compounds were found to be very active in radical formation catalyzed by all three studied enzymes. Thus, the introduction of a heterocyclic ring, even if it is bulky but flexible, on the nitrogen atom of daunosamine moiety through the one-atom spacer (amidine group), does not induce the steric hindrance effect on the interaction of daunorubicin derivatives with these flavoprotein enzymes.
14
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Pleiotropic effect of anticapsin on HeLa S_3 cells

75%
Woynarowska B., Witkowski A., Borowski E.
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issue 4
369-376
15
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Molecular modeling of singlet-oxygen binding to anthraquinones in relation to the peroxidating activity of antitumor anthraquinone drugs

64%
Liwo A., Jeziorek D., Ossowski T., Dyl D., Tempczyk A., Tarasiuk J., Nowacka M., Borowski E., Woźnicki W.
Acta Biochimica Polonica
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1995
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vol. 42
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issue 4
445-456
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