[Unusual amidation reaction of Asn-containing glycopeptide antibiotics using the coupling reagent PyBOP].

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.

[New derivatives of eremomycin containing (15)n or f atoms for NMR study].

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.

[Anthracycline antibiotics and their derivatives--inhibitors of topoisomerase I].

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.

[New conjugates of antitumor antibiotic doxorubicin with water-soluble galactomannan: synthesis and biological activity].

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.

[Structure-activity relationships in a series of semisynthetic polycyclic glycopeptide antibiotics].

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.

Structure-activity relationships in a series of semisynthetic polycyclic glycopeptide antibiotics.

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 recently discovered antiviral activity of modified glycopeptides 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.

[Synthesis and antitumor activity of new analogs of anthracycline antibiotics modified by aglycon]. / Sintez i protivopukholevaia aktivnost' novykh analogov antratsiklinovykh antiviotikov, modifitsirovannykh po aglikonu.

Anthracycline antibiotics widely used, along with their semisynthetic analogues, in human cancer chemotherapy, are O-glycosides having as aglycon 7,8,9,10-tetrahydronaphtacenequinone-5,10-with some hydroxy groups, a side chain at C-9 and sugar(s) residues, usually at C-7. The review includes the most important studies on the chemical modification of the aglycon moiety of daunorubicin, doxorubicin and carminomycin during last ten years. Activity of the compounds on experimental tumours is described and their structure-activity relationship is discussed.

[Synthesis and antineoplastic properties of anthracycline antibiotics modified by a sugar residue]. / Sintez i protivoopukholevye svoistva antratsiklinovykh antibiotikov, modifitsirovannykh po sakharnomu ostatku.

The present review (for the previous part, see Bioorganicheskaya Khimia. 1990. V. 16. No 11. P. 1445-1464) describes the most important studies in the chemical modifications of the sugar moiety of anthracycline antibiotics and their analogues during last ten years.

[Synthesis and mass-spectrometric analysis of N-cycloalkyl derivatives of carminomycin, daunorubicin and their analogs]. / Poluchenie i mass-spektrometricheskoe izuchenie N-tsikloalkil'nykh proizvodnykh karminomitsina, daunorubitsina i ikh analogov.

Condensation of carminomycin or daunorubicin with glutaric dialdehyde in the presence of NaBH3CN yielded 3'-deamino-3'-piperidinocarminomycin or 3'-deamino-3'-piperidinodaunorubicin and corresponding (13-R, S)-dihydroderivatives. To prepare similar derivatives of 14-hydroxycarminomycin or doxorubicin, 13-dimethylketals of 14-bromocarminomycin or 13-bromodaunorubicin were used in the reaction of reductive alkylation with glutaric or glycolic dialdehyde to give 3'-deamino-3'-piperidino- or 3'-deamino-3'-morpholino derivatives of 13-dimethylketals of 14-bromocarminomycin or daunorubicin, respectively. After deblocking and subsequent hydrolysis of these compounds 3'-deamino-3'-piperidino- and 3'-deamino-3'-morpholino derivatives of 13-hydroxycarminomycin or doxorubicin were prepared. Reduction of the antibiotic derivatives under mass spectrometry conditions was demonstrated.

[Glycopeptide antibiotics resistance mechanism as the basis for novel derivatives development capable to overcome resistance]. / Mekhanizm rezistentnosti k glikopeptidnym antibiotikam kak osnova sozdaniia novykh proizvodnykh, sposobnykh k preodoleniiu rezistentrnosti.

The data on the genetic and biochemical bases of bacterial resistance to antibiotics of the vancomycin-ristocetin group are summarized. Special emphasis is placed on the mechanism of resistance associated with target modification and on molecular interactions occurring upon contact of glycopeptides with normal and modified targets. The prospects for developing new derivatives active against resistant bacteria are discussed. The most rational approach to the chemical transformation of glycopeptides involves the modification of the internal "binding pocket" and the peripheral regions of the molecule that participate in the stabilization of the antibiotic-target complex. Novel semisynthetic drugs of this group active against glycopeptide-resistant enterococci are described.

[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.

[Study of the structure of anthracycline antibiotics by ERIAD mass spectrometry]. / Izuchenie stroeniia antratsiklinovykh antibiotikov metodom ERIAD mass- spektrometrii.

Fragmentation of antibiotics daunorubicin, carminomycin, doxorubicin and their semisynthetic analogues under conditions of the new mass spectrometry method ERIAD is discussed. Signals of protonated molecular ion (M + H)+ and ions of fragments are present in all the mass spectra. The results are compared with literary data obtained by means of other (EI and FAB MS) mass spectrometry methods.

[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.

[Derivatives of daunorubicin containing an inosine fragment]. / Proizvodnye daunorubitsina, soderzhashchie fragment inozina.

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.

[14-O-hemiesters and 13-hydrazones of anthracyline antibiotics of the daunorubicin series. Synthesis and cytostatic activity with respect to tumor cells sensitive or resistant to doxorubicin]. / 14-O-gemiéfiry i 13-gidrazony antratsiklinovykh antibiotikov riada daunorubitsina. Sintez i tsitostaticheskaia aktivnost' v otnoshenii opukholevykh kletok, chuvstvitel'nykh ili ustoichivykh k doksorubitsinu.

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.

[Study of dimerization of polysynthetic derivatives of the antibiotic eremomycin by ESI MS and its role in elucidating antibacterial activity]. / Izuchenie dimerizatsii polusinteticheskikh proizvodnykh antibiotika éremomitsina metodom ESU MS i ee rol' v proiavlenii antibakterial'noi aktivnosti.

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.

[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.

[Synthesis and properties of new rubomycin derivatives]. / Sintez i svoistva novykh proizvodnykh rubomitsina.

Condensation of rubomycin (daunorubicin) with respective hydrazides yielded novel substituted hydrazones: 13-cyanoacetyl hydrazone rubomycin, 13-L-phenylalanyl hydrazone rubomycin, 13-BOC-3-(uracilyl-1)-DL-alanyl hydrazone rubomycin and 13-BOC-3-(adenylyl-9)-DL-alanyl hydrazone rubomycin. With successive treatment of rubomycin with hydrazine hydrate and respective ketones novel asymmetric azines were prepared: 13-cyclopentylidene hydrazone rubomycin, 13-alpha,alpha'-dimethyl-cyclopentylidene hydrazone rubomycin and 13-(1-phenylethylidene-1) hydrazone rubomycin. 14-Adenylyl-N9-rubomycin was synthesized by interaction of 14-bromorubomycin with adenine and hydrogenation of its analog, 14-N-imidazolyl rubomycin by sodium borhydrite yielded 13-dihydro-14-N-imidazolyl rubomycin. There was observed correlation between the antimicrobial activity of the derivatives against B. mycoides and their cytostatic effect on the cells of murine leukemia NK/LI. The high in vitro activity of 13-cyclopentylidene hydrazone rubomycin showed satisfactory correlation with the results of the study on the antitumor effect in animals.

[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.

[New derivatives of carminomycin and rubomycin]. / Novye proizvodnye karminomitsina i rubomitsina.

For preparing new semisynthetic analogs of anthracycline antibiotics, hydrolysis of 13-dimethylketals of 14-bromrubomycin and 14-brom-arminomycin in solution of diluted hydrochloric acid was studied. It was shown that such hydrolysis yielded 14-chlorrubomycin and 14-chlorcarminomycin. Conditions for separating the mixture of 14-chlor- and 14-bromrubomycins and the mixture of 14-chlor- and 14-bromcarminomycins by HPLC were developed. Interaction of 14-chlorine derivatives of rubomycin and carminomycin with potassium formate in the presence of the crown ether yielded 14-formyloxy derivatives of rubomycin and carminomycin. Interaction of rubomycin and carminomycin with formic acid in the presence of N-oxysuccinimide and dicyclohexylcarbodiimide resulted in formation of N-formyl derivatives of rubomycin and carminomycin.