ABSTRACT
The coupling reagent PyBOP is widely used for the synthesis of different peptides and their amides, particularly for carboxamides of glycopeptide antibiotics of vancomycin or teicoplanin groups. The amidation reaction of the peptide core of the glycopeptide antibiotic eremomycin (I) with highly reactive amines in the presence of PyBOP is usually not accompanied by the formation of side products. However, the amidation of I with bulky amines (e.g., decyl amine and adamantyl amine) in the presence of PyBOP and Et3N or di-(i-Pr)2EtN (pH - 8.5) yielded N-unsubstituted carboxamide of eremomycin (Ia) as an admixture. The reaction of (I) or vancomycin (II) with an excess of PyBOP and Et3N (pH - 8.5) without addition of an amine or ammonia gave a mixture of products which contained higher amounts of the corresponding N-unsubstituted carboxamides (-20%). The structures of the samples of Ia and vancomycin amide (IIa) were proved by 1H NMR and ESI MS methods and confirmed by comparing with the authentic samples.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Glycopeptides/chemistry , Vancomycin/chemical synthesis , Amides/chemical synthesis , Amides/chemistry , Bacteria/drug effects , Glycopeptides/chemical synthesis , Glycopeptides/pharmacology , Humans , Molecular Structure , Organophosphorus Compounds/chemical synthesis , Organophosphorus Compounds/chemistry , Triazoles/chemical synthesis , Triazoles/chemistry , Vancomycin/chemistry , Vancomycin/pharmacologyABSTRACT
New semisynthetic derivatives of eremomycin containing (15)N or F atom were obtained for studying the antibiotic-target interaction in intact cells of Gram-positive bacteria by REDOR NMR method. Interaction of the terminal carboxyl group of amino acid 7 (AA7) of eremomycin with amines in the presence of PyBOP and TBTU reagents resulted in the corresponding [(15)N]-amide, p-fluorobenzylamide, p-fluorophenylpiperazide, and 6-N-(p-fluorobenzyl)aminohexylamide. A selective method of [(15)N]-amidation of carboxyl group of amino acid 3 (AA3) of carboxyeremomycin was developed, and the amide of eremomycin containing [(15)N] in AA3 amide group near the antibiotic binding pocket was obtained. Carboxyeremomycin bisamides substituted at AA3 and AA7 and containing two atoms of [(15)N] or F were obtained from carboxyeremomycin and [(15)N]NH4Cl or the corresponding p-fluorobenzylamine hydrochloride in the presence of PyBOP at pH ~8. The Edman degradation of eremomycin p-fluorobenzylamide gave de-(D-MeLeu)-eremomycin p-fluorobenzylamide, a hexapeptide derivative incapable of the antibiotic binding with -D-Ala-D-Ala fragment of growing cell wall peptidoglycan. Among the compounds studied, carboxyeremomycin bis-p-fluorobenzylamide showed the best activity against both the glycopeptides-sensitive and glycopeptides-resistant strains of staphylococci and enterococci.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Enterococcus/growth & development , Glycopeptides/chemical synthesis , Glycopeptides/pharmacology , Staphylococcus/growth & development , Anti-Bacterial Agents/chemistry , Drug Resistance, Bacterial/drug effects , Fluorides/chemistry , Glycopeptides/chemistry , Nitrogen Isotopes/chemistryABSTRACT
The relationship between the structure of new semisynthetic derivatives of doxorubicin, daunorubicin, and carminomycin and their ability to inhibit topoisomerase 1 were studied. The new derivatives inhibit the activity of topoisomerase 1 at low concentrations, induce the death of K-562 leukemia cells in culture, and produce an antitumor effect in experimental animals with P388 leukemia.
Subject(s)
Carubicin/analogs & derivatives , Carubicin/chemistry , Daunorubicin/analogs & derivatives , Daunorubicin/chemistry , Doxorubicin/analogs & derivatives , Doxorubicin/chemistry , Topoisomerase I Inhibitors , Animals , Carubicin/pharmacology , Daunorubicin/pharmacology , Doxorubicin/pharmacology , Drug Screening Assays, Antitumor , Humans , K562 Cells , Leukemia P388/drug therapy , Mice , Structure-Activity RelationshipABSTRACT
New water-soluble conjugates in the form of Schiff bases (DGM-1 and DGM-2) were prepared by the interaction of water-soluble periodate-oxidized galactomannan with doxorubicin or N-(L-lysyl)doxorubicin, respectively. The water-soluble galactomannan (DAVANAT a commercial product of Pro-Pharmaceuticals company) was obtained by partial acidic hydrolysis of high-molecular-mass galactomannan from Cyamopsis tetragonoloba (guar gum) seeds. The conjugate stability was studied in aqueous solutions. The DGM-1 antiproliferative activity was comparable with that of doxorubicin on three models: cell lines of murine melanoma B 16-F1, human breast cancer MCF-7 (HTB-22), and human colon cancer HT-29 (HTB-38). DGM-2 was poorly active in all the three tests. DGM- 1 can thus be regarded as a high-molecular-mass depot form of doxorubicin.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Doxorubicin/chemistry , Mannans/chemistry , Mannans/pharmacology , Animals , Antibiotics, Antineoplastic/chemical synthesis , Cell Line, Tumor , Doxorubicin/chemical synthesis , Doxorubicin/pharmacology , Galactose/analogs & derivatives , Humans , Mannans/chemical synthesis , Mice , Solubility , Water/chemistryABSTRACT
The main achievements in the development of methods for the design of semisynthetic antibiotics of a new generation belonging to the group of polycyclic glycopeptides directed against infections caused by multidrug-resistant bacteria and dangerous human and animal viruses are reviewed. The review is focused on the results obtained at the Gauze Institute in the area of chemical modification of natural antibiotics (eremomycin, vancomycin, teicoplanin, etc.) directed toward modification of their antibacterial and/or antiviral activity. A special emphasis is placed on the study of the mechanisms of action of these antibiotics, which could be the basis of a rational approach to their chemical modification involving the transformation of the inner binding pocket and the peripheral regions of the molecules that participate in the formation of their complexes with targets. The study of the recently discovered antiviral activity of modified glycopeptide antibiotics is also discussed. A possibility of obtaining new highly active anti-HIV-1 and anti-HIV-2 preparations on the basis of hydrophobic derivatives of the aglycones of glycopeptide antibiotics was demonstrated. New semisynthetic derivatives of antibiotics that exhibit a high antibacterial activity in vivo, have good pharmacological characteristics, and are promising for practical use are described.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Glycopeptides/chemistry , Glycopeptides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Glycopeptides/chemical synthesis , Peptides, Cyclic/chemistry , Structure-Activity RelationshipABSTRACT
Ascorbigen, a natural product, is an indole derivative of L-ascorbic acid. Its effect on postnatal development and antibacterial resistance of the small intestine was studied on newborn mice. Ascorbigen was administered to 3-5-day old mice in a dose of 100 mg/kg orally every day for 7-10 days. 30 minutes before the last administration of the drug clinical isolates of Staphylococcus aureus or Escherichia coli were administered intragastrically to the young mice. The animals were killed in 24 hours and the frequency of the isolation of the microbes from the blood, spleen, kidneys and liver was developed. The oral use of the drug normalized the intestinal microflora, provided a reliable decrease of the bacteria isolation from the blood, spleen, kidneys and liver and prevented the animal death. The morphological examination showed that ascorbigen significantly increased the number and activity of the Paneth cells in the gland crypts, the goblet cells in the villi and mononuclear cells in the selfplate of the intestine mucous membrane vs. the intact control.
Subject(s)
Ascorbic Acid/analogs & derivatives , Indoles/pharmacology , Intestinal Mucosa/cytology , Intestinal Mucosa/microbiology , Intestine, Small/drug effects , Administration, Oral , Animals , Animals, Newborn , Ascorbic Acid/administration & dosage , Ascorbic Acid/pharmacology , Blood/drug effects , Blood/microbiology , Enteritis/drug therapy , Enteritis/microbiology , Escherichia coli/pathogenicity , Female , Indoles/administration & dosage , Intestinal Mucosa/drug effects , Intestine, Small/microbiology , Kidney/drug effects , Kidney/microbiology , Liver/drug effects , Liver/microbiology , Mice , Mice, Inbred Strains , Spleen/drug effects , Spleen/microbiology , Staphylococcus aureus/pathogenicityABSTRACT
Eremomycin derivatives with benzylated amino groups of both residues of eremosamine and with (R) or (S)-2-amino-4-methylpentyl substituted for N-methyl-D-Leu, the first amino acid residue of its heptapeptide, were synthesized to study the role of the peptide bond between the first and the second amino acid residues of the heptapeptide moiety of the antibiotic in its interaction with the precursors of the bacterial cell wall peptidoglycan and exhibition of its antibacterial activity. Comparison of the antibacterial activities of N',N"-dibenzyleremomycin, de-(N-methyl-D-Leu)-N',N"-dibenzyleremomycin, and its N-(2-amino-4-methylpentyl)-derivative (1,2-deoxo-N',N"-dibenzyleremomycin) demonstrated that cleavage or replacement of the first amino acid residue by the corresponding aminoalkyl residue results in a decrease in its antibacterial activity towards both vancomycin-sensitive and vancomycin-resistant strains of microorganisms. The English version of the paper.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Glycopeptides , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Peptides/chemistry , Structure-Activity RelationshipABSTRACT
The dimerization constants for glycopeptide antibiotics vancomycin, ristocetin, and eremomycin and nine semisynthetic eremomycin derivatives were determined by the electrospray ionization mass spectrometry; the constants for natural antibiotics turned out to be close to those previously determined by NMR. No correlation between these dimerization constants and antibacterial activities of all the compounds toward the clinical strains of Gram-positive bacteria was found.
Subject(s)
Anti-Bacterial Agents/chemistry , Glycopeptides , Anti-Bacterial Agents/pharmacology , Dimerization , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Spectrometry, Mass, Electrospray IonizationABSTRACT
The chemical background of the biological activities of vegetables of the Cruciferae family is considered. These vegetables contain alkaloids of the glucobrassicin group that are decomposed by the enzyme myrosinase (thioglucosidase, EC 3.2.3.1) released upon damage to the plant cells. This results in several indole derivatives, with ascorbigen and indole-3-carbinol predominating. In the gastrointestinal tract, these compounds form 5H,11H-indolo[3,2-b]carbazole, natural ligand of the aromatic hydrocarbon receptor (Ah receptor) and a functional analogue of 2,3,7,8-tetrachlorodibenzo-p-dioxin, a dangerous xenobiotic. The indolocarbazole-Ah receptor complex activates the gene of CYP1A1, an isoenzyme of cytochrome P450-dependent monoamine oxidase, which enhances the 2-hydroxylation (inactivation) of estrogens. In its turn, the resulting lowered level of estrogens inhibits the growth of hormone-dependent tumors or prevents their appearance. The mechanism of xenobiotic inactivation, underlying the anticarcinogenic action of food products including vegetables of Cruciferae family and some homogeneous indole compounds, is similar. Some other effects of nutrient indole compounds, e.g., the inhibition of expression of the cyclin-dependent kinase 6 (CDK6) by indole-3-carbinol that leads to the cell cycle arrest in G1 phase, are also considered. Analysis of the biological effects of the Cruciferae diet has helped start clinical studies of indole-3-carbinol as an antitumor and anticarcinogenic remedy for patients with a high risk of tumor diseases.
Subject(s)
Brassicaceae/metabolism , Indoles/metabolism , Indoles/chemistryABSTRACT
New methods for the chemical modification of clinically important glycopeptide antibiotics are reviewed. Special emphasis is placed on chemical modification of the domestic antibiotic eremomycin, which has a number of advantages over the clinically used antibiotics vancomycin and teichoplanin. The most promising methods for glycopeptide modification at the aromatic ring and carboxyl group of the seventh amino acid of the peptide core and also at the amino groups of the carbohydrate moiety are discussed in detail. The structure-activity relations in a series of glycopeptide derivatives are revealed. It is shown that the presence of lipophilic substituents of certain structures and sizes is mandatory for activity toward glycopeptide-resistant enterococci to be displayed. The possibility of dimerization and interaction of these derivatives with membrane components of the bacterial cell wall is discussed. The structures of the derivatives most active toward glycopeptide-resistant enterococci and meticillin-resistant staphylococci are presented.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Drug Resistance, Microbial , Enterococcus/drug effects , Glycopeptides , Ristocetin/chemistry , Ristocetin/pharmacology , Structure-Activity Relationship , Teicoplanin/chemistry , Teicoplanin/pharmacology , Vancomycin/analogs & derivatives , Vancomycin/chemistry , Vancomycin/pharmacologyABSTRACT
A new approach for the modification of the heptapeptide core of glycopeptide antibiotics was proposed based on the replacement of amino acid residues in positions 1 and 3 in teicoplanin aglycone and in position 1 in the eremomycin aglycone. Six novel nonnatural aglycones of the vancomycin type were obtained. Compounds derived from the teicoplanin aglycone exhibited in vitro activity against Gram-positive bacteria, and two of them were also active against the vancomycin-resistant enterococci.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Vancomycin/analogs & derivatives , Vancomycin/pharmacology , Vancomycin/chemistryABSTRACT
Doxorubicin and 14-hydroxycarminomycin 14-O-hemiadipates and 14-O-hemipimelates, synthesized from 14-bromo derivatives of daunorubicin and carminomycin and monosodium adipate and pimelate, were converted to the corresponding N-trifluoroacetylated compounds. 13-(4-Methylpiperazine-1-yl)imino derivatives of the anthracycline antibiotics were also obtained. The cytostatic activity of the compounds synthesized was studied using a panel of human and animal tumor cell lines sensitive or resistant to doxorubicin. N-Trifluoroacetylation of the antibiotics resulted in a decrease in the cytostatic activity. The activity of the water-soluble 13-(4-methylpiperazine-l-yl)imino derivatives is close to that of the corresponding parent antibiotics.
Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Daunorubicin/chemistry , Doxorubicin/pharmacology , Animals , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Cell Division/drug effects , Daunorubicin/pharmacology , Drug Resistance, Neoplasm , Esters , Humans , Hydrazones/chemistry , Leukemia P388/pathology , Tumor Cells, CulturedABSTRACT
In experiments with mice radioprotective effect of N-methylascorbigen was revealed. DRF calculated from survival data was 1.16 when N-methylascorbigen (100 mg/kg) was administered i/p 24 h before irradiation.
Subject(s)
Ascorbic Acid/analogs & derivatives , Indoles/pharmacology , Radiation Injuries, Experimental/prevention & control , Radiation-Protective Agents , Animals , Ascorbic Acid/administration & dosage , Ascorbic Acid/pharmacology , Indoles/administration & dosage , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Radiation Dosage , Radiation Injuries, Experimental/mortality , Time FactorsABSTRACT
The reaction of 2'-deoxy-5-trimethylsilyl(Tms)uridine with methanesulfonyl chloride led to the corresponding 3',5'-di-O-mesyl derivative, which was treated with lithium toluylate in DMF to give 2,3'-anhydro-1-(2-deoxy-5-O-p-toluyl-beta-D-xylofurano- syl)-5-Tms-uracil. Under these conditions 1-(2,3-dideoxy-5-O-p-toluyl-alpha-D- glycero-pent-2-enofuranosyl)-5-Tms-uracil was obtained from 1-(2-deoxy-alpha-D-ribofuranosyl)-5-Tms-uracil. Interaction of 2,3'-anhydronucleoside with LiN3 in DMF and successive deacylation with MeONa-MeOH gave 3'-azido-2',3'-dideoxy-5-Tms-uridine. Hydrogenation of this compound with 10% Pd/C in ethanol gave 3'-azido-2',3'-dideoxy-5-Tms-uridine. From 2,4,5-tris-Tms-uracil and 2,3-didehydrofurane in 1,2-dichloroethane in the presence of SnCl4 1-(2-tetrahydrofuranyl)-5-Tms-uracil was prepared. In a similar way 1-[(1,3-dioxy-2-propoxy)methyl]-5-Tms-uracil was synthesized by condensation of silylated uracil with 1,3-dibenzyloxy-2-acetoxymethylglycerol followed by the hydrogen transfer hydrogenolysis with cyclohexene--20% Pd(OH)2/C. None of the compounds exhibits cytotoxic activity against CaOv in vitro. The acycloderivative in concentration of 250 micrograms/ml has no effect on the HSV-1 and vaccinia virus replication in vitro. 3'-Azidonucleoside in dose of 100-750 mg/kg as well as 1-(2-tetrahydrofuranyl)-5-Tms-uracil in dose of 160-800 mg/kg were devoid of antitumour activity against P388 in vivo.
Subject(s)
Antimetabolites , Glycosides/chemistry , Nucleosides/chemistry , Trimethylsilyl Compounds/chemistry , Uracil/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Indicators and Reagents , Leukemia P388 , Nucleosides/pharmacology , Simplexvirus/drug effects , Simplexvirus/physiology , Trimethylsilyl Compounds/pharmacology , Uracil/pharmacology , Vaccinia virus/drug effects , Vaccinia virus/physiology , Virus Replication/drug effectsABSTRACT
Methyl, benzyl and diphenylmethyl esters of the glycopeptide antibiotic eremomycin were obtained by its treatment with corresponding diazoalkanes. The esters have high antibacterial activity but are less active than the parent antibiotic.
Subject(s)
Anti-Bacterial Agents , Anti-Infective Agents , Esters/chemistry , Carboxylic Acids/chemistry , Chromatography, High Pressure Liquid , Glycopeptides/chemical synthesis , Glycopeptides/pharmacology , Magnetic Resonance Spectroscopy , Spectrophotometry, InfraredABSTRACT
A mutant strain of the bruneomycin-producing culture which produced up to 10% of the minor component was selected. The component was identified as streptonigrone. It was isolated and its physicochemical properties and antibacterial activity were investigated. Trimethylsilyl derivatives of streptonigrone and bruneomycin were prepared. Their PMR spectra and electron impulse mass spectra were studied. Streptonigrone was shown to have antibacterial and cytotoxic activities which was 1 to 2 orders of magnitude lower than that of bruneomycin.
Subject(s)
Streptonigrin/analysis , Bacillus/drug effects , Bacillus subtilis/drug effects , Escherichia coli/drug effects , Models, Chemical , Saccharomyces cerevisiae/drug effects , Staphylococcus aureus/drug effects , Streptonigrin/pharmacologyABSTRACT
Derivatives of antitumour anthracycline antibiotics containing N-methylurea moiety in the carbohydrate ring were obtained by the interaction of methyl isocyanate with daunorubicin, doxorubicin, carminomycin and daunorubicin derivatives, substituted at C-13 or C-14 positions. N-Nitrosation of these compounds yielded modified anthracycline antibiotics containing the N-methyl-N-nitrosourea substituent at C-3' position. Alkaline degradation of these derivatives produced, through corresponding isocyanates cyclic 3'-N,4'-carbonylderivatives. In these anthracycline derivatives with sugar cycles conjugated with oxazoline-2-ones the predominant conformations of sugar ring has changed from 1C4 to 4C1, 2,5B, or B0,3 (shown by 1H NMR spectroscopy). It was demonstrated, both in vitro and in vivo, that introduction of methylurea or cytotoxic methylnitrosourea moieties does not potentiate antimicrobial, cytotoxic or antitumour properties of these compounds.
Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Daunorubicin/chemical synthesis , Leukemia P388/drug therapy , Leukemia, Experimental/drug therapy , Methylnitrosourea/chemical synthesis , Methylurea Compounds/chemical synthesis , Animals , Cell Division/drug effects , Chemical Phenomena , Chemistry , Daunorubicin/pharmacology , Male , Mice , Structure-Activity RelationshipABSTRACT
Condensation of daunorubicin or its (13 R, S)-dihydro derivative with inosine dialdehyde in the presence of NaBH3CN yielded novel derivatives of anthracycline antibiotics with incorporated inosine residue: 3'-deamino-3'-[(2" R)-(hypoxanthyl-9)-(6" S)-hydroxymethylmorpholino-N4"]- daunorubicin and (13 R,S)-dihydro-3'-deamino-3'-[(2" R)-(hypoxanthyl-9)-(6" S)- hydroxymethylmorpholino-N4"]-daunorubicin. The compounds did not inhibit growth of Bacillus mycoides and were less cytotoxic in vitro and less toxic in vivo than the parent antibiotics.
Subject(s)
Daunorubicin/analogs & derivatives , Inosine , Antibiotics, Antineoplastic/pharmacology , Bacillus/drug effects , Chemical Phenomena , Chemistry , Daunorubicin/pharmacology , Magnetic Resonance SpectroscopyABSTRACT
Perspectives of search, among natural and semisynthetic antibiotics, for inhibitors of different stages of the human immunodeficiency virus replication are discussed. The compounds which inhibit the virus absorbtion, reverse transcription, viral mRNA synthesis, viral protein translation or viral glycoprotein processing are presented.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antiviral Agents , HIV/drug effects , Chemical Phenomena , Chemistry , Drug Evaluation, PreclinicalABSTRACT
Streptomyces grisoruber strain 1618-306 produces three types of anthracycline antibiotics, derivatives of epsilon-pyrromycinone (methyl (7S, 9R, 10R)-9-ethyl-5,7,8,9,10,12-hexahydro-1,4,6,7,9-pentahydroxy-5,12-di oxo-10- naphthacenecarboxylate), epsilon-1-hydroxyauramycinone and epsilon-1-hydroxysulfurmycinone, differing in C-9 substituent in D ring of anthracyclines (Et, Met or CH2COCH3, respectively). Besides 7-O-glycosides of these aglycones, complex of antibiotics contains corresponding 7-deoxy- and 7,8,9,10-bisanhydroanthracyclinones.