[The structure of antibiotic eremomycin B].

A new biologically active component, antibiotic eremomycin B, was isolated from the culture liquid of Amycolatopsis orientalis subsp. eremomycini, the producing strain for antibiotic eremomycin. Its structure was established by NMR spectroscopy and mass spectrometry. Eremomycin B was shown to differ from eremomycin by the presence of an N-carboxymethyl substituent in the disaccharide eremosamine fragment.

Chemical modification of antibiotic eremomycin at the asparagine side chain.

AA3-Carboxyeremomycin 2, obtained by selective hydrolysis of antibiotic eremomycin was used as a starting compound for the eremomycin chemical modifications at the asparagine side chain to be transformed into eremomycin AA3, AA7 bis-amides (3a-c). Bis-benzylamide 3b displayed an activity (8 microg/ml) against an E. faecium VanA strain.

A modification of the N-terminal amino acid in the eremomycin aglycone.

An Edman degradation of the antibiotic eremomycin aglycone produced the corresponding hexapeptide, which was aminoacylated with D-lysine, D-histidine or D-tryptophan derivatives to give new heptapeptide analogs of the eremomycin aglycone. The aminoacylation of the eremomycin aglycone produced an octapeptide analog. The substitution of D-lysine for the N-terminal N-methyl-D-leucine does not seriously affect the in vitro antibacterial properties of the eremomycin aglycone whereas the heptapeptides with the N-terminal D-tryptophan or D-histidine moieties and the octapeptide with the N-terminal D-lysine are practically devoid of the antibacterial properties.

Carboxamides and hydrazide of glycopeptide antibiotic eremomycin. Synthesis and antibacterial activity.

Carboxamides and hydrazide of glycopeptide antibiotic eremomycin were obtained by a direct reaction of the carboxy group of eremomycin with an appropriate amine or hydrazine using diphenyl phosphorazidate as a condencing agent. Eremomycin hydrazide was also obtained by hydrazinolysis of the eremomycin methyl ester. Use of dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide for amidation led to the corresponding eremomycin ureides. The ESI-MS data indicate that eremomycin and its amides exist as dimers. The carboxamide, methylamide and benzylamide of eremomycin were as active against Gram-positive bacteria as the parent antibiotic, and the methylamide, benzylamide and hydrazide were almost an order of magnitude more active than eremomycin against Staphylococcus epidermidis clinical isolates in vitro. Amide of eremomycin as well as ureides were devoid of histamine liberating properties, which demonstrates that protection of the carboxyl group leads to a decrease in the allergenic properties.

Modification of glycopeptide antibiotic eremomycin by the action of alkyl halides and study on antibacterial activity of the compounds obtained.

Alkylation of glycopeptide antibiotic eremomycin by the action of different alkyl halides leads, depending on the structure of alkyl halides used, to eremomycin derivatives of six types; alkylated at the N-terminus, quaternary compounds at the N-terminus, eremomycin esters, esters of eremocycin alkylated at the N-terminus, esters of eremomycin quaternised at the N-terminus, esters of eremomycin alkylated both at the N-terminus and at the aminogroup of disaccharide branch. Five compounds demonstrated high antibacterial activity in vitro, N-allyleremomycin and methyl ester of N,N-dimethyleremomycin being at least as good as the parent eremomycin.

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.

An NMR study of eremomycin and its derivatives. Full 1H and 13C assignment, motional behavior, dimerization and complexation with Ac-D-Ala-D-Ala.

Complete 1H and 13C NMR assignments are presented for eremomycin (1) and some of its desglycosylated derivatives 2, 3 and compared to the structurally closely related glycopeptide vancomycin. Primary structure and stereochemistry of eremomycin is corroborated by the present high field total correlation spectroscopy, NOESY and heteronuclear multiple-bond correlation NMR methods. A rough motional characterization of the title compound is attempted by 13C-T1 and 13C-[1H] NOE measurements. Dimerization of eremomycin is observed both in DMSO-d6-CCl4 and D2O solutions. Complexation with cell wall analogue dipeptide Ac-D-Ala-D-Ala is also demonstrated.

[Synthesis and antibacterial activity of eremomycin esters through the carboxyl group]. / Sintez i antibakterial'naia aktivnost' éfirov antibiotika po karboksil'noi gruppe.

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.

[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.

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.

[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.

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

Eremomycin is shown to be a new representative of the group of polycyclic glycopeptides. By the amino acid composition it is close to vancomycin but by the structure of triphenoxytriaminotricarboxylic acid it differs from vancomycin. Monodechlorovancomycinic acid was detected in eremomycin. On the basis of the data obtained in studies on the amino acid sequence and the molecule functional groups the structural formula of eremomycin aglycon was assigned. It is demonstrated that the chlorine-containing phenylserine fragment of monodechlorovancomycin acid is located in the N-end region of the aglycon peptide chain.

[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.

[Structure of the tricyclic triaminotricarboxylic acid (Y) from the antibiotic actinoidin]. / Stroenie trekh"iadernoi triaminotrikarbonovoi kisloty (Y) iz antibiotika aktinoidina.

The products of triaminotricarboxylic acid (Y) transformation in alkaline and reduction (HI/P) hydrolysis and the PMR spectra of the Y-Phe dipeptide were studied and the nature of the 3 amino acid substitutes and their position in the aromatic nuclei were determined. With regard to the data on the structure of the aromatic skeleton published earlier the structure of the Y amino acid as 3-(2-chlor-4-seryl-phenoxy)-5-(4-seryl-phenoxy)-p-hydroxyphenylglycine was suggested. The presence of 2 alcoholic groups of the phenylserine fragments of the Y amino acid in the actinoidine aglycone was shown with additional acetylation (Ac2O/Py) of N-acetylmethoxyaglycone. It was found with O-acetylation of N-acetylmethoxyactinosaminyl aglycone that the actinosamine amino sugar in the actinoidine molecule was bound with one of the above groups.

[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.

[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.

[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.