[Reaction of acylation of the antineoplastic antibiotic bleomycetin]. / Issledovanie reaktsii atsilirovaniia protivoopukholevogo antibiotika bleomitsetina.

The reaction of benzoylation of bleomycetin, a glycopeptide antibiotic, and its cuprum complex was studied with the chloranhydride and carbodiimide methods. Acylation of the antibiotic cuprum complex by an equivalent quantity of benzoyl chloride resulted in formation of a mixture of mono- and disubstituted derivatives while with the use of a 3-fold excess of chloranhydride it was possible to obtain dibenzoylbleomycetin as a sole reaction product. Interaction of the bleomycetin cuprum complex with activated benzoic ether resulted in formation of a product monosubstituted by the antibiotic spermidine fragment. After acylation of the free antibiotic by the carbodiimide and chloranhydride methods tri- and tetrabenzoyl derivatives of bleomycetin were isolated respectively.

[Chemical modification of an antineoplastic antibiotic bleomycetin by the C-end fragment]. / Khimicheskaia modifikatsiia protivoopukholevogo antibiotika bleomitsetina po C-kontsevomu fragmentu.

Bleomycetin, an antitumor antibiotic, was subjected to chemical modification by the C-end fragment i.e. the residue of 3-[(4-aminobutyl)amino]propylamine (spermidine++) with acylation, carbamoylation and reducing alkylation, which yielded its new semisynthetic derivatives. The use of physicochemical methods showed that the chemical modification involved the primary and secondary amino groups++ of spermidine++ and gave rise to N,N'-diacyl, N,N'-dicarbamoyl and N,N'-dialkyl bleomycetins. The biological properties of the derivatives, i.e. their cytotoxic activity, acute and pulmonary toxicities were studied. The transformation of bleomycetin by the C-end fragment lowered the antibiotic toxicity and was believed to be a promising approach to modifying its molecule.

[The structure and antimicrobial activity of the partial degradation products of the antibiotic eremomycin]. / Struktura i antimikrobnaia aktivnost' produktov chastichnoi degradatsii antibiotika éremomitsina.

Antimicrobial activity of partial degradation products of eremomycin, a new glycopeptide antibiotic, was studied. The products formed by eremomycin deglycosylation (deseremosaminyl eremomycin, eremosaminyl aglycone and aglycone) and elimination of the chlorine atom from the molecule aglycone moiety (dechloroeremomycin). The spectral data in favour of the compounds structure are presented. It was found that partial degradation led to a decrease in the antimicrobial activity of the antibiotic. Dechloreremomycin had the highest activity among the products. Its MIC for the methicillin-resistant strains of Staphylococcus aureus was only twice as low as that of the initial antibiotic.

[Results of the surgical treatment of patients with primary tuberculosis]. / Rezul'taty khirurgicheskogo lecheniia bol'nykh pervichnym tuberkulezom.

The analysis of treatment of 163 patients with primary forms of tuberculosis in the Southern Crimea sanatorium (1967-1987) is given. Along with the operation techniques used for a removal of the affected intrathoracic and peripheric lymph nodes, the details of the patients' preoperative management, occurred complications and their treatment as well as immediate outcomes of these efforts are illustrated. The analysis was made in accordance with forms of the disease, age distribution and types of intervention. During preoperative period and afterwards, the involvement of climatic factors favourably influenced the course of the postoperative stage. The management of patients with tuberculosis of the mesenteric lymph nodes is presented also.

Eremomycin--new glycopeptide antibiotic: chemical properties and structure.

By a combination of chemical and spectroscopic (1H and 13C NMR) studies the structure of a glycopeptide antibiotic eremomycin has been elucidated. It is closely related to vancomycin, but differs in sugar and chlorine content. The eremomycin aglycone contains monodechlorovancomycinic acid; the only chlorine atom is situated in the second amino acid after the N-terminal amino acid residue of the peptide. The sugar part is composed of glucose and two residues of an amino sugar shown to be 2,3,6-trideoxy-3-amino-C-3-methyl-L-arabino-hexopyranose (4-epi-vancosamine). One of the amino sugar residues is a component of the disaccharide 2-O-(alpha-L-4-epi-vancosaminyl)-beta-D-glucopyranose, attached to a triphenyl ether moiety; the position of another one is at the serine oxygen in the C-terminal region of the aglycone.

[Eremomycin--a new antibiotic of the polycyclic glycopeptide group]. / Eremomitsin--novyi antibiotik gruppy politsiklicheskikh glikopeptidov.

Eremomycin is a novel antibacterial antibiotic. It was isolated at the Institute of New Antibiotics, the USSR Academy of Medical Sciences from the culture fluid of actinomycete INA-238. By its physico-chemical and biological properties the antibiotic was classified as belonging to the group of polycyclic glycopeptides. Chemical structure of eremomycin was asserted and it was shown to be a new representative of the group close by its structure to vancomycin and differing from it by the carbohydrate composition and structure of tri-phenoxytriaminotricarboxylic acid. By its anti-bacterial spectrum eremomycin was found to be close to ristomycin and vancomycin. Still, its activity was 2-10 times higher. The antibiotic was several times less toxic than vancomycin. Unlike vancomycin and ristomycin, the novel antibiotic induced no tissue necrosis after its intramuscular administration. The chemotherapeutic indices of eremomycin in treatment of staphylococcal and streptococcal sepsis in albino mice exceeded 10 times those of vancomycin. At present eremomycin is under clinical trials.

[Modification of eremomycin by amine groups]. / Modifikatsiia éremomitsina po aminnym gruppam.

Possible modification of eremomycin, a novel glycopeptide antibiotic by the amine groups with acylating agents such as Ac2O/MeOH and CH3(CH2)7COCl/Et3N and alkylating agents such as CH3CHO, NaBH and NaBH3CN was studied. N-Acetyl, N,N'-diacetyl. N-pelargoil, N-ethyl, N,N'-diethyl and N,N',N"-triethyl derivatives of eremomycin were prepared. Their structure was asserted and the order of the substitute introduction was determined. The antimicrobial activity against Bacillus subtilis and Staphylococcus aureus was assayed. It was found that with introduction of the ethyl substitutes to the eremomycin molecule the antibiotic activity lowered insignificantly whereas the acylation resulted in its decreasing by 1-2 orders.

[The structure of eremomycin, a new antibiotic of the group of polycyclic glycopeptides]. / Struktura éremomitsina--novogo antibiotika gruppy politsiklicheskikh glikopeptidov.

Structure of the carbohydrate moiety of the eremomycin molecule was assessed. Two residues of eremosamine were detected in the antibiotic. One of them in the composition of 2-0-(L-eremosaminyl)-D-glucopyrazone dissaccharide was linked by the phenol group to monodechlorvancomycinic acid and the other formed the monosaccharide branch by the alcohol group of the same acid at the peptide C-end area. On the basis of the results of the present study and the data published earlier (structure of the aglycone and aminosugar) the structure of eremomycin was assigned.

[Structure of eremosamine--an amino sugar from the antibiotic eremomycin]. / Struktura éremozamina--aminosakhara iz antibiotika éremomitsina.

A new amino sugar named eremosamine was isolated from hydrolysate of eremomycin, an antibiotic belonging to the group of polycyclic glycopeptides. Crystalline derivatives of the amino sugar i. e. methyleremosaminide and methyl-N,O-acetyleremosaminide (alpha- and beta-anomers) were prepared. The data on PMR study and optic properties of the compounds showed that eremosamine had the structure of 2,3,6-tridesoxy-3-amino-3-C-methyl-L-arabinohexose.

[Structure of actinoidins A and B]. / Struktura aktinoidinov A i B.

The sequence of the amino acid residues in the peptide chain of aglycone was shown on the basis of the data concerning the splitting of actinoidin aglycon and the products of its partial acid hydrolysis by various methods. It was found that the free COOH-group of actinoidin belonged to he glycine residue of the dioxyphenyl nucleus of actinoidinic amino acid. The site of the actinosamine attachment to aglycon was determined. The final structure of actinoidins A and B is suggested.

[Spatial configuration of the carbohydrate portion of carminomycins II and III]. / Prostranstvennaia konfiguratsiia uglevodnoi chasti karminomitsinov II i III.

A neutral fragment of the carbohydrate part of the molecule was isolated in the form of a cyclic acetal (3.5-dinitrobenzoate) from carminomycins II and III belonging to anthracyclines. The acetal preserved all the asymmetric centers. Methanolysis of the cyclic acetal resulted in formation of aldol dimethyl acetal and propylene glycol (3,5-dinitrobenzoate) with isolated asymmetric centers. On the basis of the optic and spectral properties of these compounds it was found that carminomycins II and III differed in the configuration of 2 asymmetric carbon atoms, i.e. acetal atom and the atom in propylene glycol. They had configurations of R (--) in carminomycin II and S (+) in carminomycin III. The third asymmetric center of the acetal in both antibiotics was the same, i.e. S(+).

[Carbohydrate linkage with the peptide portion of the ristomycin A molecule]. / Sviaz' uglevodov s peptidnoi chast'iu molekuly ristomitsina A.

The mannose monosaccharide residue in ristomycin A is bound via C-3 phenolic oxygen of the 1,2,3,5-substituted ring with actinoidinic amino acid. The tetrassacharide branch is attached to the only phenolic oxygen of triaminotricarboxylic acid. The ristosaminyl residue is linked via one of the two aliphatic hydroxyl groups of the same amino acid. By the location of neutral carbohydrates risotmycin A does not differ from ristocetin A.

[Revision of the structure of ristomycinic and actinoidinic amino acids]. / Utochnenie strultury ristomitsinovoi i aktinoidinovoi aminokislot.

The structures of ristomycin and actinoidine amino acids described earlier were revised. Crystalline derivatives of the amino acids and the products of their oxidation were prepared. The study on the spectral properties of the compounds showed that ristomycin and actinoidine amino acids had the structures of 3-(2'-hydroxy-5'-glycyl-phenoxy)-4-methyl-5-hydroxyphenylglycine and 2-(2'-hydroxy-5'-glycyl-phenyl)-3,5-dioxyphenylglycine respectively. They did not differ from deaminodicarboxylic acids prepared with ristocetin, vancomycin and actionoidine.

[Structure of the carbohydrate moiety of carminomycins II and III]. / Struktura uglevodnoi chasti karminomitsinov II i III.

Saccharides II and III were obtained on catalytic hydrogenolysis of carminomycins II and III. The saccharides contained daunosamine and a nitrogen-free fragment of unknown structure. Crotonic aldehyde in the form of 2,4-dinitrophenylhydrazone and 1,2-propylenglycol in the form of 3,5-dinitrobenzoate were isolated on acid hydrolysis of the saccharides. The study on the chemical and spectral properties (PMR-spectra) of the saccharides, their N,O-acetates and hydrolysis products suggested the structure of th carbohydrate moiety of carminomycins II and III as a disaccharide of daunosamine and acyclic semiacetal of 2,4-desoxytetrose.

[Triaminotricarboxylic amino acid oxidation productions of actinoidin and ristomycin]. / Produkty okisleniia triaminotrikarbonovykh aminokislot aktinoidina i ristomitsina.

Aromatic acids with three benzene nuclei bound through oxygen were obtained from actinoidin and ristomycin on their oxydation with permanganates of methylated aglycones and peptides. The structures of the methyl esters of these acids were determined by spectral methods. They are the following: methyl-3,5-bis-(4-methoxycarbonyl-phenoxy)-4-methoxybenzoate (from ristomycin) and methyl-3-(2-chlor-4-methoxycarbonyl-phenoxy)-5-(4-methoxycarbonyl-phenoxy)-4-methoxybenzoate (from actinoidin). The compounds are the aromatic parts of the molecules of the unusual triaminotricarboxylic amino acids present in the aglycones of all antibiotics of the group of polycyclic glycopeptides.

[Quantitative amino acid makeup and the characteristics of the amino groups of ristomycin and the products of its partial acid hydrolysis]. / Kolichestvennyi aminokislotnyi sostav i kharakteristika aminogrupp ristomitsina i produktov ego chastichnogo kislotnogo gidroliza.

The quantitative amino acid composition of ristomycin A, a glycopeptide antibiotic, peptides I-IV (from partial acid hydrolysis of the antibiotic) and their dinitrophenylic derivatives was determined. It was shown that both ristomycin and free peptides I-IV contained one residue of ristomycinic acid and one residue of actinoidinic acid, diamino-dicarbonic amino acids of the glycylphenolic type. Peptides I-IV had close molecular weights, i.e. 1100-1200 and differed from each other in the gradually increasing numbers of NH2- and COON- groups, from one in peptide I to four in peptide IV. The quantitative amino acid analysis of the dinitrophenylic derivatives of ristomycin and peptides I-IV showed that the free NH2-group in peptide I belonged to ristomycinic acid, the same as in the antibiotic, while in peptides III-IV at least one of the free NH2-groups belonged to ristomycinic acid and the other belonged to actinoidinic acid.

[Carbohydrate bond to the hydroxyaromatic amino acids in actinoidins A and B]. / O sviazi uglevodov s oksiaromaticheskimi aminokislotami v aktinoidinakh A i B.

The method of exhaustive methylation with diasomethane was used as applied for actinoidines A and B and their glycosides for elucidation of the problem of connection between the carbohydrates and oxyaromatic fragments of the antibiotics followed by analysis of the acid hydrolyzates of the methoxy derivatives. It was found that the disaccarhide branch, i.e. 2-O-(L-acozaminyl)-D-glucose was connected in actinoidines A and B through the phenol group of the triaminotricarbonic fragment V, while the residue of D-mannose was connected through one of the phenol groups of the actinoidinic amino acid. The other two phenolic groups of the actinoidinic amino acid, as well as the phenolic groups of the N-end amino acids did not participate ion formation of the glycoside bonds. Actinosamine was probably connected through the alcohol group of the aglycone.