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Biomedical subjects

E Borowski

Publications and source records attributed to E Borowski.

At least 91 records · Page 5Linked to original sources
PubMed1988

Synthesis and antileukemic activity of N-enamine derivatives of daunorubicin, 5-iminodaunorubicin, and doxorubicin.

Eleven N-enamine derivatives of daunorubicin and of its 5-imino analogue as well as of doxorubicin have been synthesized and evaluated for antileukemic activity in vitro and in vivo. Comparison of biological activities of examined compounds with other enamine derivatives of daunorubicin, reported earlier by us, has indicated that the optimal activity is shown by N-(1-carboethoxypropen-1-yl-2)daunorubicin.

Animals↗
PubMed1988

Antifungal peptides with novel specific inhibitors of glucosamine 6-phosphate synthase.

N3-4-Methoxyfumaroyl-L-2,3-diaminopropanoic acid (FMDP) has been found to be a strong and selective inhibitor of glucosamine 6-phosphate synthase from Candida albicans. Incorporation of FMDP into a dipeptide structure has produced effective antifungal agents (portage transport). A number of dipeptides containing FMDP have been synthesized, with Nva-FMDP showing the highest in vitro activity against different fungi, including Candida albicans (MIC90 = 2.2 micrograms/ml for 50 clinical strains), Cryptococcus neoformans and Aspergillus spp. This compound, when tested in a general candidiosis model infection in mice, gave PD50/10 and CD50/10 values of 5.0 and 1.63 mg/kg, respectively. Meanwhile, the LD50 value after i.v. administration was higher than 300 mg/kg.

Alanine↗
PubMed1988

An alternative concept for the molecular nature of the peroxidating ability of anthracycline anti-tumor antibiotics and anthracenodiones.

Quantum chemical calculations of model anthraquinone molecules using the CNDO/2 method have revealed that superoxide anion radical formation following the single electron transfer mediated by anthraquinone anti-tumor antibiotics may occur in aerobic conditions as a result of the direct addition of an electron to the anthraquinone-oxygen low energy charge transfer complex that is formed with singlet oxygen. Cyclovoltammetric measurements have been performed in order to provide experimental evidence supporting the hypothesis. The structural requirements for an anthraquinone molecule not exhibiting peroxidating ability by the above mechanism have been postulated. They include maximum symmetry of electron density distribution (symmetry of the molecule), a decrease of the electron density of the pi electron system and an increase in the rigidity of the molecule.

Anthraquinones↗
PubMed1988

Structural basis for the binding of antitumor anthracycline antibiotics to model membranes: circular dichroism studies.

Circular dichroism was used to compare the binding of several anthracycline antitumor antibiotics to sonicated phosphatidylcholine vesicles. Daunorubicin analogues, differing from the parent by structural changes in the amino sugar moiety of the molecule, were tested both with vesicles that contained negatively charged phospholipids and with neutral vesicles. The self-association properties of the analogues were also investigated. Binding to negatively charged vesicles was not strictly dependent on electrostatic interactions, since the characteristics of daunorubicin binding were totally different from those of Adriamycin (doxorubicin). Furthermore, the cardiotoxicity of these molecules did not have its origin in their quantitatively preferential electrostatic binding to negatively charged cardiolipin-containing membranes: DR-19, a daunorubicin derivative having lower cardiotoxicity than the parent compound, which bound to negatively charged vesicles in a manner quite similar to that of Adriamycin, whereas DR-10, another daunorubicin derivative with higher cardiotoxicity, bound poorly to negatively charged vesicles.

Cholesterol↗
PubMed1987

Synthesis and biological properties of N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid dipeptides, a novel group of antimicrobial agents.

A series of dipeptides with N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP), the irreversible inhibitor of glucosamine-6-phosphate synthetase from bacteria and fungi, have been synthesized and their antibacterial and antifungal properties in vitro evaluated. The results demonstrate that these peptides inhibit the growth of a number of the tested microorganisms, especially pathogenic fungus Candida albicans. The results of competitive antagonism studies indicate specific peptide transport of the peptides via peptide permeases as drug delivery system and gives evidence for the high selectivity of the action upon the cells, as a result of the inhibition of generation of glucosamine.

Amino Acids, Diamino↗
PubMed1987

Antitumor activity of new N-substituted daunorubicin derivatives.

The biological properties of two new structural groups of modification products of daunorubicin, the N-glycosyl and enamino derivatives, were investigated. The activities of the compounds were characterized in vitro (yeasts and leukaemia cells) and in vivo (L1210 leukaemia in mice). Among the compounds studied DR-19, N-(1-carboethoxypropen-1-yl)daunorubicin, exhibited activity comparable with that of the parent antibiotic. The correlation coefficients calculated showed good correlation between in vitro tests. In vitro activity and potency (reciprocal of optimal dose) in mice leukaemia were also correlated. However, no correlation between the in vitro activity and activity in mice leukaemia (increase of life span) was observed.

Animals↗
PubMed1987

Pleiotropic effect of anticapsin on HeLa S3 cells.

Anticapsin, the terminal epoxyaminoacid moiety of tetaine, inhibits irreversibly growth of HeLa S3 cells. The antibiotic decreases to a similar extent incorporation of 3H-labelled precursors into nucleic acids and protein in intact cells: inhibition of protein synthesis prevails on prolonged incubation. Also incorporation of [3H]dTTP and [3H]UTP is inhibited in the presence of anticapsin into permeabilized cells. These effects, however, are not due to the interference with DNA or RNA polymerases since anticapsin only slightly suppresses RNA polymerase activity and has no effect on DNA polymerase in the cell-free systems. The results indicate that the mechanism of antiproliferative action of anticapsin in HeLa S3 cells differs from that of tetaine and imply that inhibition of protein synthesis might be the primary effect of anticapsin.

Alanine↗
PubMed1986

Inactivation of glucosamine-6-phosphate synthetase from Salmonella typhimurium LT2 by fumaroyl diaminopropanoic acid derivatives, a novel group of glutamine analogs.

A novel group of glutamine analogs, N3-fumaroyl-L-2,3-diaminopropanoic acid (FDP) and its derivatives and analogs including amide (FCDP), methyl ester (FMDP) and its homologue, N4-(4-methoxyfumaroyl)-L-2,4-diaminobutanoic acid, inactivate glucosamine-6-phosphate synthetase (L-glutamine: D-fructose-6-phosphate aminotransferase (hexose-isomerizing), EC 2.6.1.16), isolated from Salmonella typhimurium, by covalent modification. For comparative purposes, selected known glutamine analogs were also examined. Anticapsin, 6-diazo-5-oxo-L-norleucine and, at high concentration, azaserine inactivate the enzyme. The pseudo-first-order rate constants show a hyperbolic dependence on inhibitor concentration for all the above-mentioned inhibitors, suggesting the formation of a reversible complex prior to covalent modification. Dissociation constants for inhibitors were determined and ranged from 10(-4) M for FCDP to 10(-6) M for FMDP. Albizziin, gamma-glutamylhydroxamate and, at low concentration, azaserine inhibit glucosamine synthetase only reversibly. All inhibitors tested are competitive in relation to glutamine. and competitive inhibitors, albizziin and gamma-glutamylhydroxamate protect the enzyme against inactivation. Fructose 6-phosphate accelerates the rate of inactivation. Some analogs of FDP, such as SMDP, CRDP, O-FMSer, MMDP and AADP, are not active against glucosamine-6-phosphate synthetase. The structure-activity relationship of the novel group of glutamine analogs is discussed and structural requirements for the activity of these compounds is established. It is postulated that the compounds examined can be classified as mechanism-based enzyme inactivators.

Alanine↗
PubMed1986

Antibiotic tetaine--a selective inhibitor of chitin and mannoprotein biosynthesis in Candida albicans.

The antibiotic tetaine inhibits in Candida albicans the biosynthesis of two important cell wall constituents, chitin and mannoprotein. This effect is a consequence of inactivation of the enzyme glucosamine-6-phosphate synthetase. Due to the lack of glucosamine-6-phosphate the effective secretion of mannoprotein enzymes, acid phosphatase and invertase, by Candida albicans spheroplasts is inhibited. In the presence of tetaine, probably a modified mannoprotein, lacking a branched polymannan, is synthesized. The antibiotic action decreases the viability of Candida albicans cells, especially that of mycelial forms of this fungus.

Anti-Bacterial Agents↗
PubMed1986

Synthesis of N3-fumaramoyl-L-2,3-diaminopropanoic acid analogues, the irreversible inhibitors of glucosamine synthetase.

Several analogues of N3-fumaramoyl-L-2,3-diaminopropanoic acid were synthesized and evaluated for inhibition of glucosamine-6-phosphate synthetase activity. The syntheses were accomplished by acylation reaction of N2-tert.-butoxycarbonyl-L-2,3-diaminopropanoic acid (Boc-A2pr) or N2-tert.-butoxycarbonyl-L-2,4-diaminobutanoic acid (Boc-A2-bu) with the N-succinimidoyl esters of several derivatives of alpha, beta-unsaturated acids 2a-d followed by deprotection of the Boc groups. The obtained compounds were tested for inhibition of glucosamine synthetase isolated from Salmonella typhimurium and Saccharomyces cerevisiae. The results indicated that among the synthesized compounds, N3-4-methoxyfumaroyl-L-2,3-diaminopropanoic acid (FMDP) was the most powerful inhibitor of glucosamine synthetase.

Alanine↗
PubMed1986

Bacteriolytic effect of cessation of glucosamine supply, induced by specific inhibition of glucosamine-6-phosphate synthetase.

The antibiotic tetaine (bacilysin) and its C-terminal epoxyaminoacid--anticapsin--are powerful inhibitors of glucosamine-6-phosphate synthetase (EC 5.3.1.19.) in cell-free extracts of Escherichia coli K-12. Tetaine acts on growing cells as a bactericidal agent. This bactericidal action, measured from 10 to 160 muM concentration, is a consequence of the induction of lysis of growing cells. The induction of lysis by tetaine is compared with the lytic action of some beta-lactams. Hypertonic medium, destruction of the antibiotic, presence of chloramphenicol or the addition of N-acetylglucosamine protect E. coli K-12 cells against lysis induced by tetaine. These effects are compared with those observed in the presence of penicillin G. The results indicate that inhibition of early or late stages of peptidoglycan synthesis all result in more or less the same consequence, i.e. death via cell lysis.

Anti-Bacterial Agents↗
PubMed1986

Anticapsin: an active site directed inhibitor of glucosamine-6-phosphate synthetase from Candida albicans.

L-beta-(2,3-epoxycyclohexanono-4)-alanine, an active fragment of the antibiotic tetaine, identical to the antimetabolite anticapsin, is a powerful inhibitor of partially purified glucosamine-6-phosphate synthetase (2-amino-2-deoxy-D-glucose-6-phosphate ketol isomerase, aminotransferring, EC 5.3.1.19) from pathogenic fungus Candida albicans. Anticapsin was demonstrated to be a competitive inhibitor of this enzyme with respect to L-glutamine and uncompetitive with respect to D-fructose-6-phosphate. Incubation of anticapsin with glucosamine-6-phosphate synthetase in the absence of glutamine led to the formation of an inactive enzyme, irreversibly modified. The inactivation obeyed saturation kinetics; the determined Kinact was 9.5 X 10(-6) M. Addition of glutamine protected the enzyme against inactivation by anticapsin. Reaction of anticapsin with the enzyme exhibited characteristics of affinity labelling of the glutamine binding site. Probably the inactivation proceeds via an alkylation of cysteine residue at the glutamine binding site.

Alanine↗
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↗
PubMed1986

New N-amino acid derivatives of daunorubicin.

New N-amino acid derivatives of daunorubicin have been obtained by acylation of daunorubicin amino group with alpha, beta, and gamma amino acids and their N,N-dibenzyl derivatives. The results of the antitumor activity determination have evidenced that the change of the amino function position in the daunorubicin derivatives, in relation to that of the parent antibiotic, causes the loss of activity.

Animals↗