The formation of 2-hydroxy-4-hydroxymethyl-3-(indol-3-yl)-cyclopent-2-enone derivatives from ascorbigens.

A facile preparation is described of 3-(indol-3-yl)-2-hydroxy-4-hydroxymethylcyclopent-2-enone and its N-derivatives in 15-40% yields by the degradation of ascorbigen or its N-derivatives in a warm solution of L-ascorbic acid through a sequential domino reaction. The same cyclopentenone derivatives were obtained in 30-40% yields by the condensation of (N-alkylindol-3-yl)glycolic acids with ascorbic acid. 2,6-Dihydroxy-1-(indol-3-yl)hexa-1,4-diene-3-one and 2-hydroxy-4-hydroxymethyl-5-(indol-3-yl)cyclopent-2-enone were identified as intermediates in this reaction.

A new type of chemical modification of glycopeptides antibiotics: aminomethylated derivatives of eremomycin and their antibacterial activity.

A series of derivatives of eremomycin aminomethylated at the 7d position of the resorcinol ring of the amino acid No. 7 was prepared by interaction of eremomycin with formaldehyde and various primary and secondary amines and ammonia. The most active compound obtained was 7d-decylaminomethyl derivative, whose minimal inhibitory concentrations for clinical isolates of staphylococci are 2 approximately 8 times lower than those of the parent antibiotic. 7d-Decylaminomethyl derivative was also active against vancomycin-resistant VanA enterococci (8 microg/ml) and Neisseria gonorrhoeae (16 microg/ml).

Transformation of streptonigrin into streptonigrone; synthesis and biological evaluation of antibiotics streptonigrin and streptonigrone alkyl ethers.

A method of synthesis of antibiotic streptonigrin 8'-O-alkyl ethers by alkylation of streptonigrin diphenylmethyl ester and consequent deprotection of carboxylic group with CF3COOH is developed. An attempt to deblock carboxylic group of 8'-O-methylstreptonigrin diphenylmethyl ester by hydrogenation over Pd produced 8'-O-methylstreptonigrone. Similarly streptonigrin was transformed into streptonigrone over Pd-black in H2 stream. Methylation of streptonigrone afforded 5',5'-N-dimethyl-2',8'-O-dimethylstreptonigrone and 1',5',5'-tri-N-trimethyl-8'-O-methylstreptonigrone. Alkyl streptonigrin ethers demonstrated lower antibacterial activity in vitro than the parent antibiotic.

Synthesis and cytostatic properties of daunorubicin derivatives, containing N-phenylthiourea or N-ethylthiourea moieties in the 3'-position.

A series of phenylthiourea and ethylthiourea derivatives of daunorubicin and its congeners was prepared by reaction of the 3'-amino group of the antibiotic with phenylisothiocyanate or ethylisothiocyanate. S-Methylation yielded S-methylisothiouromium salts which when reacted with amines resulted in an intramolecular cyclization with the participation of the neighboring 4'-OH group. The structures and predominant conformations of the thiourea derivatives and daunorubicino(3'-N,4'-O-d)oxazolines were determined by 1H and 13C NMR. Cytostatic activities of the thiourea and oxazoline derivatives were compared with the cytostatic activities of N-methylurea and N-methyl-N-nitrosourea containing daunorubicin and its congeners. Carminomycin derivatives were endowed with the highest cytostatic activity.

167-A, a new antibiotic produced by a mutant of an inactive wild strain of Amycolata autotrophica.

Two related antibiotics, 167-A and 167-B, were isolated from the fermentation broth of a mutant of an inactive wild strain of Amycolata autotrophica. Antibiotic 167-B was found to be cervinomycin A2; antibiotic 167-A is a new representative of the same group and has the structure of 18-O-demethyl cervinomycin A2.

Synthesis and biological activity of derivatives of glycopeptide antibiotics eremomycin and vancomycin nitrosated, acylated or carbamoylated at the N-terminal.

Nitrosation, carbamoylation or acylation of the glycopeptide antibiotics eremomycin or vancomycin produced series of derivatives substituted at the N-terminus of the peptides. Though the modified amino group in these derivatives is not capable of protonation, N-nitroso derivatives retain antibacterial activity in vitro and in vivo. N-Carbamoyleremomycin has low activity, and N-Cbz-eremomycin and N-Boc-eremomycin are devoid of antibacterial activity, both in vitro and in vivo.

Substitution of amino acids 1 and 3 in teicoplanin aglycon: synthesis and antibacterial activity of three first non-natural dalbaheptides.

The replacement of amino acids 1 and 3 of glycopeptide antibiotics (dalbaheptides) with new amino acids or other chemical entities suitable to interact with both glycopeptide-resistant (D-Ala-D-Lactate) and susceptible (D-Ala-D-Ala) targets is one of the chemical strategies currently followed to pursue activity against highly glycopeptide-resistant VanA enterococci while maintaining activity against glycopeptide-susceptible Gram-positive bacteria, particularly methicillin-resistant staphylococci. As a preliminary approach, the substitution of amino acid 1 of deglucoteicoplanin (TD) with D-lysine or D-methylleucine and of its amino acid 3 with L-phenylalanine or L-lysine was investigated. In this paper, the synthesis and in vitro antibacterial activities of first non-natural dalbaheptide methyl ester aglycons MDL 63,166 (D-Lys1-Phe-3-TD-DHP-Me), MDL 64,945 (D-Lys1-Lys3-TD-DHP-Me), and MDL 64,468 (D-MeLeu1-Lys3-TD-DHP-Me) are described. These compounds, which were obtained from intermediate TD-derived tetrapeptide methyl ester (TDTP-Me) according to a 9-step overall procedure, had excellent anti-staphylococcal activity. The most active derivative against staphylococci, MDL 64,945 (MIC: 0.063 microgram/ml for S. aureus, S. epidermidis and S. haemolyticus) was inactive against VanA enterococci, while MDL 63,166 and MDL 64,468 were somewhat active against VanA strains of E. faecalis; MDL 64,468 was also moderately active against one VanA isolate of E. faecium and had marginal activity as TD against E. coli.

Polyfunctional indole-3-carbinol derivatives: 1-(indol-3-yl)glycerols and related compounds, beta-hydroxytryptamines and ascorbigens. Chemistry and biological properties.

Earlier interaction of indole-3-carbinols with L-ascorbic acid and chemical and biological properties of formed 2-skatylderivatives of L-ascorbic acid (ascorbigens) were discussed. In this presentation the properties and stereochemistry of products of interaction of polyfunctional biologically important indole-3-carbinols (indoleglycerol analogs and beta-hydroxytryptamine derivatives) with L-ascorbic acid are investigated. Biological significance of this reaction is discussed.

[Antibiotic N',N''-dibenzyleremomycin with reduced 1,2-peptide bond]. / Antibiotik N',N''-dibenzyléremomitsin s vosstanovlennoi 1,2-peptidnoi sviaz'iu.

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.

[Non-natural aglycones of glycopeptide antibiotics of the vancomycin group. Synthesis and antibacterial activity]. / Neprirodnye aglikony glikopeptidnykh antibiotikov vankomicinovoi gruppy. Sintez i izuchenie antibakterial'noi aktivnosti.

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.

[Derivatives of antineoplastic antibiotics of the daunorubicin series containing methylurea or nitrosomethylurea residues]. / Proizvodnye protivoopukholevykh antibiotikov riada daunorubitsina, soderzhashchie ostatok metilmocheviny ili nitrozometilmocheviny.

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.

[Induction of antibiotic production in inactive cultures of actinomycetes. Monensin production by a mutant strain 2608 EB-1]. / Induktsiia obrazovaniia antibiotikov neaktivnymi kul'turami aktinomitsetov. Obrazovanie monenzina mutantnym shtammom 2608 EB-1.

An actinomycete strain designated as 2608 was isolated from a soil sample. When cultivated on various solid and liquid media, the strain was inactive. The strain exposure to ethidium bromide resulted in formation of a mutant producing an antibiotic active against some gram-positive bacteria. The property of the antibiotic production proved to be stable. The antibiotic was identified by IR, NMR and mass spectroscopy as monensin. Strain 2608 producing monensin differs from the described monensin-producing culture Streptomyces cinnamonensis ATCC 15413 and is a new culture producing monensin.

[Rubomycin Q1--an anthracycline metabolite from Streptomyces coeruleorubidus 2679, a strain producing rubomycin C]. / Rubomitsin Q1--antratsiklinovyi metabolit iz rubomitsin c-produtsiruiushchego shtamma Streptomyces coeruleorubidus 2679.

In the programme of screening of biologically active secondary metabolites produced by Streptomyces coeruleorubidus 2679 a new reddish-violet component (rubomycin Q1) with antibacterial and cytotoxic activity was isolated from the culture fluid of the organism. Some physico-chemical and biological properties of a chromatographically pure rubomycin Q1 were investigated. It was shown with the use of 1H NMR, UV, IR and mass spectrometry that rubomycin Q1 was an anthracycline antibiotic (9,10-anhydro-13-desoxycarminomycin).