RESUMO
A comprehensive comparative analysis of the structure-antifungal activity relationships for the series of biosynthetically engineered nystatin analogues and their novel semisynthetic derivatives, as well as amphotericin B (AMB) and its semisynthetic derivatives, was performed. The data obtained revealed the significant influence of the structure of the C-7 to C-10 polyol region on the antifungal activity of these polyene antibiotics. Comparison of positions of hydroxyl groups in the antibiotics and in vitro antifungal activity data showed that the most active are the compounds in which hydroxyl groups are in positions C-8 and C-9 or positions C-7 and C-10. Antibiotics with OH groups at both C-7 and C-9 had the lowest activity. The replacement of the C-16 carboxyl with methyl group did not significantly affect the in vitro antifungal activity of antibiotics without modifications at the amino group of mycosamine. In contrast, the activity of the N-modified derivatives was modulated both by the presence of CH3 or COOH group in the position C-16 and by the structure of the modifying substituent. The most active compounds were tested in vivo to determine the maximum tolerated doses and antifungal activity on the model of candidosis sepsis in leukopenic mice (cyclophosphamide-induced). Study of our library of semisynthetic polyene antibiotics led to the discovery of compounds, namely, N-(L-lysyl)-BSG005 (compound 3n) and, especially, L-glutamate of 2-(N,N-dimethylamino)ethyl amide of S44HP (compound 2j), with high antifungal activity that were comparable in in vitro and in vivo tests to AMB and that have better toxicological properties.
Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Polienos/farmacologia , Animais , Antifúngicos/síntese química , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Ciclofosfamida/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Leucopenia/induzido quimicamente , Leucopenia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Nistatina/análogos & derivados , Nistatina/farmacologia , Polienos/síntese química , Sepse/tratamento farmacológico , Sepse/microbiologia , Bibliotecas de Moléculas Pequenas/análise , Relação Estrutura-AtividadeRESUMO
A novel way of chemical modification of the antibiotic olivomycin A (1) at the side chain of the aglycon moiety was developed. Interaction of olivomycin A with the sodium periodate produced the key acid derivative olivomycin SA (2) in 86% yield. This acid was used in the reactions with different amines in the presence of benzotriazol-1-yl-oxy-trispyrrolidino-phosphonium hexafluorophosphate (PyBOP) or diphenylphosphoryl azide (DPPA) to give corresponding amides. Whereas olivomycin SA was two orders of magnitude less cytotoxic than the parent antibiotic, the amides of 2 demonstrated a higher cytotoxicity. In particular, N,N-dimethylaminoethylamide of olivomycin SA showed a pronounced antitumor effect against transplanted experimental lymphoma and melanoma and a remarkably high binding constant to double stranded DNA. The therapeutic effects of this derivative were achievable at tolerable concentrations, suggesting that modifications of the aglycon's side chain, namely, its shortening to methoxyacetic residue and blocking of free carboxyl group, are straightforward for the design of therapeutically applicable derivatives of olivomycin A.
Assuntos
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/uso terapêutico , Animais , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , Feminino , Humanos , Linfoma/tratamento farmacológico , Melanoma/tratamento farmacológico , Camundongos , Olivomicina/química , Olivomicina/farmacologia , Olivomicina/uso terapêuticoRESUMO
Novel derivatives of tris(indol-3-yl)methane and tris(indol-3-yl)methylium salts with the alkyl substituents at the N-atoms of the indole rings were synthesized. An easy substitution of indole rings in trisindolylmethanes for other indoles under the action of acids is demonstrated, and the mechanism of substitution is discussed. To obtain trisindolylmethylium salts, the environmentally safe method of oxidation of trisindolylmethanes with air oxygen in acidic conditions was developed. Tris(1-alkylindol-3-yl)methanes and tris(1-alkylindol-3-yl)methylium salts represent three-bladed molecular propellers whose physico-chemical and biological properties strongly depend on the N-alkyl substituent. The cytotoxicity of novel compounds increased with the number of C atoms in the alkyl chains, with optimal number n=3-5 whereas the derivatives with longer side chains were less cytotoxic. The most potent novel compounds killed human tumor cells at nanomolar-to-submicromolar concentrations, being one order of magnitude more potent than the prototype antibiotic turbomycin A [tris(indol-3-yl)methylium salt]. Apoptosis in HCT116 colon carcinoma cell line induced by tris(1-pentyl-1H-indol-3-yl)methylium methanesulfonate was detectable at concentrations tolerable by normal blood lymphocytes. Thus, N-alkyl substituted tris(1-alkylindol-3-yl)methylium salts emerge as perspective anticancer drug candidates.
Assuntos
Antineoplásicos/síntese química , Indóis/química , Metano/análogos & derivados , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Humanos , Indóis/síntese química , Indóis/toxicidade , Metano/química , Sais/químicaRESUMO
A variety of semisynthetic derivatives of natural antibacterial glycopeptide antibiotics such as vancomycin, eremomycin, ristocetin A, teicoplanin A(2)-2, DA-40926, their aglycons, and also the products of their partial degradation with a destroyed or modified peptide core show marked anti-retroviral activity in cell culture. In particular, aglycon antibiotic derivatives containing various substituents of a preferably hydrophobic nature displayed activity against human immunodeficiency virus type 1 (HIV-1), HIV-2, and Moloney murine sarcoma virus at a 50% inhibitory concentration in the lower micromolar (1-5 microM) concentration range while not being cytostatic against human lymphocytic cells at 250 microM or higher. The mode of anti-HIV action of the antibiotic aglycon derivatives could be ascribed to inhibition of the viral entry process.
Assuntos
Antibacterianos/química , Antivirais/síntese química , Glicopeptídeos , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Vírus do Sarcoma Murino de Moloney/efeitos dos fármacos , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Efeito Citopatogênico Viral/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/virologia , Humanos , Camundongos , Relação Estrutura-AtividadeRESUMO
Des-(N-methyl-D-leucyl)eremomycin was obtained by Edman degradation of eremomycin. Derivatives with a hydrophobic substituent at the exterior of the molecule were then synthesized, and their antibacterial activities were compared with similar derivatives of eremomycin. Comparison of derivatives of eremomycin containing the n-decyl or p-(p-chlorophenyl)benzyl substituent in the eremosamine moiety (N') and n-decyl or p-(p-chlorophenyl)benzylamides with similar derivatives of eremomycin possessing the damaged peptide core (a defective binding pocket) showed that compounds of both types are almost equally active against glycopeptide-resistant strains of enterococci (GRE), whereas eremomycin derivatives are more active against staphylococci. Hydrophobic 7d-alkylaminomethylated derivatives of eremomycin (9, 10) demonstrated similar antibacterial properties. Since the basic mode of action of glycopeptide antibiotics involves binding to cell wall intermediates terminating in -D-Ala-D-Ala and this interaction is seriously decreased in the hexapeptide derivatives (lacking the critical N-methyl-D-leucine), we suggest that these hydrophobic derivatives may inhibit peptidoglycan synthesis in the absence of dipeptide binding. NMR binding experiments using Ac-D-Ala-D-Ala show that binding constants of these hexapeptide derivativies are decreased in comparison with the corresponding heptapeptides with intact binding pocket. This is in agreement with the decreased biological activity of the hexapeptide derivatives against vancomycin-sensitive strains in comparison with the activity of parent compounds. Binding to the lactate cell wall analogue Ac-D-Ala-D-Lac with decylamide of eremomycin 8 was not observed, demonstrating that the interaction with this target in GRE does not occur. While hydrophobic glycopeptide derivatives retain the ability to inhibit the synthesis of peptidoglycan in manner of natural glycopeptides, biochemical investigation supports the hypothesis that they inhibit the transglycosylase stage of bacterial peptidoglycan biosynthesis even in the absence of dipeptide or depsipeptide binding.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Glicopeptídeos/síntese química , Glicopeptídeos/farmacologia , Antibacterianos/química , Enterococcus/efeitos dos fármacos , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Ressonância Magnética Nuclear Biomolecular , Peptidoglicano/biossíntese , Staphylococcus aureus/efeitos dos fármacos , Propriedades de SuperfícieRESUMO
Alkaline degradation of the ascorbigen 2-C-[(indol-3-yl)methyl]-alpha-L-xylo-hex-3-ulofuranosono-1,4-lactone (1a) led to a mixture of 1-deoxy-1-(indol-3-yl)-L-sorbose (2a) and 1-deoxy-1-(indol-3-yl)-L-tagatose (3a). The mixture of diastereomeric ketoses underwent acetylation and pyranose ring opening under the action of acetic anhydride in pyridine in the presence of 4-dimethylaminopyridine (DMAP) with the formation of a mixture of (E)-2,3,4,5,6-penta-O-acetyl-1-deoxy-1-(indol-3-yl)-L-xylo-hex-1-enitol (4a) and (E)-2,3,4,5,6-penta-O-acetyl-1-deoxy-1-(indol-3-yl)-L-lyxo-hex-1-enitol (5a), which were separated chromatographically. Deacetylation of 4a or 5a afforded cyclised tetrols, tosylation of which in admixture resulted in 1-deoxy-1-(indol-3-yl)-3,5-di-O-tosyl-alpha-L-sorbopyranose (12a) and 1-deoxy-1-(indol-3-yl)-4,5-di-O-tosyl-alpha-L-tagatopyranose (13a). Under alkaline conditions 13a readily formed 2-hydroxy-4-hydroxymethyl-3-(indol-3-yl)cyclopenten-2-one (15a) in 90% yield. Similar transformations were performed for N-methyl- and N-methoxyindole derivatives.
Assuntos
Ácido Ascórbico/análogos & derivados , Hexoses/síntese química , Sorbose/análogos & derivados , Álcalis , Ácido Ascórbico/química , Indóis/química , Espectroscopia de Ressonância Magnética , Sorbose/síntese químicaRESUMO
A series of olivomycin A derivatives containing different combinations of the acyl residues in the carbohydrate chains was obtained. The formation of complexes of Mg(2+)-coordinated dimers of these compounds with double-stranded DNA was studied using spectral methods such as absorption, fluorescence and circular dichroism (CD) spectral analyses. There was a good correlation of the values of binding constants of complexes (antibiotic)2Mg(2+)-DNA, the quantum yields of fluorescence and changes of the induced CD spectra with topoisomerase I inhibition and cytotoxicity. We demonstrate that the presence of the acyl groups in the saccharide residues of olivomycin A derivatives is absolutely necessary for a high cytotoxic potency of these antibiotics. On the basis of the experimental results and quantum chemical calculations, we presume that the acyl residue in the 4-O-position in the A-sugar residue is involved, to the most part, in the antibiotic-antibiotic interactions in the (olivomycin)2Mg(2+) dimers, whereas the O-acyl group in E-olivomicose residue largely participates in the formation of the (olivomycin)2Mg(2+)-DNA complexes.
Assuntos
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Carboidratos/química , Carboidratos/farmacologia , Antibióticos Antineoplásicos/metabolismo , Cátions Bivalentes/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Magnésio/metabolismo , Olivomicina/química , Olivomicina/farmacologiaRESUMO
Mono- and disubstituted novel derivatives of the heptaene nystatin analog 28,29-didehydronystatin A(1) (S44HP, 1) were obtained by chemical modification of the exocyclic C-16 carboxyl and/or an amino group of mycosamine moiety. The strategy of preparation of mono- and double-modified polyene macrolides was based on the use of intermediate hydrophobic N-Fmoc (9-fluorenylmethoxycarbonyl) derivatives that facilitated the procedures of isolation and purification of new compounds. The antifungal activity of the new derivatives was first tested in vitro against yeasts and filamentous fungi, allowing the selection of the most active compounds that were subsequently tested for acute toxicity in mice. 2-(N,N-dimethylamino)ethylamide of 1 (2) and 2-(N,N-dimethylamino)ethylamide of N-fructopyranosyl-28,29-didehydronystatin A(1) (2a) were then selected for further evaluation in a mouse model of disseminated candidosis, and showed high efficacy while being considerably less toxic than amphotericin B (AmB). The compound with improved water solubility (2G, L-glutamic acid salt of 2) showed better chemotherapeutic activity than AmB in the mouse model of candidosis sepsis on a leucopenic background. Very low antifungal effect was seen after treatment with AmB, even if it was used in maximum tolerated dose (2 mg kg(-1)). Unlike AmB, compound 2G exhibited high activity in doses from 0.4 up to 4.0 mg kg(-1), despite leucopenic conditions.
Assuntos
Antifúngicos/química , Antifúngicos/uso terapêutico , Candidíase/tratamento farmacológico , Nistatina/análogos & derivados , Sepse/tratamento farmacológico , Animais , Antifúngicos/efeitos adversos , Engenharia Genética , Dose Letal Mediana , Masculino , Camundongos , Estrutura Molecular , Nistatina/efeitos adversos , Nistatina/química , Nistatina/uso terapêutico , Sepse/microbiologia , Relação Estrutura-AtividadeRESUMO
Twenty-three new derivatives of the heptaene nystatin analogue 28,29-didehydronystatin A(1) (1) (S44HP) were obtained by chemical modification of C16 carboxyl and amino groups of mycosamine. These derivatives comprised 15 carboxamides, 4 N-alkyl derivatives, 3 N-derivatives containing additional N-linked monosaccharide or disaccharide moiety (products of Amadori rearrangement), and 1 N-aminoacyl derivative. The derivatives have been tested in vitro against yeasts Candida albicans, Cryptococcus humicolus, and filamentous fungi (molds) Aspergillus niger and Fusarum oxysporum, as well as for hemolytic activity against human erythrocytes. Structure-activity relationships for the compounds obtained are discussed. The most active and least hemolytic derivative 3-(N,N-dimethylamino)propylamide of S44HP (6) was tested for acute toxicity and antifungal activity in animal model. Whereas amphotericin B and S44HP were active in vivo at doses close to the maximal tolerated dose, 6 was considerably less toxic and more active compared to these two antibiotics.
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Macrolídeos/síntese química , Nistatina/análogos & derivados , Polienos/síntese química , Polienos/farmacologia , Antifúngicos/química , Engenharia Genética , Macrolídeos/química , Macrolídeos/farmacologia , Espectroscopia de Ressonância Magnética , Viabilidade Microbiana/efeitos dos fármacos , Estrutura Molecular , Nistatina/síntese química , Nistatina/química , Nistatina/farmacologia , Polienos/químicaRESUMO
Aminomethylation of 9b,10-dihydro-1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino-[1,7-a]indole-1,3(2H)-diones or 1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino[1,7-a]indole-1,3(2H)-diones resulted in dialkylaminomethyl derivatives. Alkylation of the nitrogen atom of maleimide moiety of polyannelated diazepines with 1,3-dibromopropane and subsequent reaction with thiourea or its N-alkyl derivatives gave isothiourea-carrying compounds. The compounds containing isothiourea moiety were active against individual human serine/threonine and tyrosine kinases at low micromolar concentrations. Dialkylaminomethyl derivatives of diazepines sensitized Streptomyces lividans with overexpressed aminoglycoside phosphotransferase type VIII (aphVIII) to kanamycin by inhibiting serine/threonine kinase(s) mediated aphVIII phosphorylation.