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1.
Nucleosides Nucleotides Nucleic Acids ; 39(1-3): 349-364, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31566068

RESUMEN

Tunicamycins, which are nucleoside natural products, inhibit both bacterial phospho-N-acetylmuraminic acid (MurNAc)-pentapeptide translocase (MraY) and human UDP-N-acetylglucosamine (GlcNAc): polyprenol phosphate translocase (GPT). The improved synthesis and detailed biological evaluation of an MraY-selective inhibitor, 2, where the GlcNAc moiety was modified to a MurNAc amide, has been described.


Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Transferasas/antagonistas & inhibidores , Tunicamicina/síntesis química , Tunicamicina/farmacología , Proteínas Bacterianas/química , Línea Celular , Técnicas de Química Sintética , Humanos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Relación Estructura-Actividad , Transferasas/química , Transferasas (Grupos de Otros Fosfatos Sustitutos)
2.
J Antibiot (Tokyo) ; 72(12): 924-933, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31235901

RESUMEN

Tunicamycins are nucleoside natural products and show antibacterial, antiviral and antitumor activities, which are attributed to their inhibition of enzymatic reactions between polyisoprenyl phosphate and UDP-GlcNAc or UDP-MurNAc-pentapeptide. Because of their various intriguing biological activities, tunicamycins have potential as therapeutic agents for infectious diseases or cancers. Structurally, tunicamycins have a unique structure composed of an undecodialdose skeleton, a lipid chain and a GlcNAc fragment linked by a 1,1-ß,α-trehalose-type glycosidic bond. In this mini review, we summarize the total chemical syntheses and biosynthetic studies of tunicamycins.


Asunto(s)
Streptomyces/metabolismo , Tunicamicina/biosíntesis , Tunicamicina/síntesis química , Familia de Multigenes , Streptomyces/genética
3.
Angew Chem Int Ed Engl ; 54(22): 6618-21, 2015 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-25873339

RESUMEN

The tunicamycins constitute a delicate mimic of the bisubstrate intermediates of N-acetyl-D-hexosamine-1-phosphate translocases and thus inhibit bacterial cell-wall synthesis and the N glycosylation of eukaryotic proteins. An efficient approach to the synthesis of this unique type of nucleoside antibiotics is now reported and features the assembly of five modules in a highly stereoselective and robust manner. A Mukaiyama aldol reaction, intramolecular acetal formation, gold(I)-catalyzed O and N glycosylation, and final N acylation were used as the key steps.


Asunto(s)
Tunicamicina/síntesis química , Acilación , Aldehídos , Antibacterianos/síntesis química , Antibacterianos/química , Catálisis , Glicosilación , Oro/química , Estereoisomerismo , Tunicamicina/química
4.
Artículo en Inglés | MEDLINE | ID: mdl-16247947

RESUMEN

Herbicidin B and fully prtected tunicaminyluracil, which were undecose nucleoside antibiotics, were synthesized using a samarium diiodide (SmI2) mediated aldol reaction with the use of alpha-phenylthioketone as an enolate. The characteristics of the SmI2-mediated aldol reaction are that the enolate can be regioselectively generated and the aldol reaction proceeds under near neutral condition. This reaction is proved to be a powerful reaction for the synthesis of complex nucleoside antibiotics. The synthesis of caprazol, the core structure of caprazamycins, was conducted by the strategy including beta-selective ribosylation without using a neighboring group participation and the construction of a diazepanone by a modified reductive amination. Our synthetic route would provide a range of key analogues with partial structures to define the pharmacophore, which can be a lead for the development of more effective anti-bacterial agents.


Asunto(s)
Antibacterianos/síntesis química , Nucleósidos/síntesis química , Uracilo/síntesis química , Adenosina/análogos & derivados , Adenosina/síntesis química , Química Farmacéutica/métodos , Diseño de Fármacos , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Yoduros/farmacología , Cetonas/farmacología , Modelos Químicos , Nucleósidos de Purina/síntesis química , Samario/farmacología , Tunicamicina/análogos & derivados , Tunicamicina/síntesis química
5.
Artículo en Inglés | MEDLINE | ID: mdl-15043150

RESUMEN

A tunicaminyluracil derivative, which is a key component of the tunicamycin nucleoside antibiotics, was synthesized using a samarium diiodide (SmI2) mediated aldol reaction and intramolecular Pummerer reaction as the key steps. The alpha-phenylthio ketone 11, the precursor of the samarium enolate, was prepared from D-galactose. Treatment of 11 with SmI2 at -40 degrees C resulted in complete conversion to the corresponding samarium enolate, and subsequent addition of uridine 5'-aldehyde 12 afforded the desired aldol products 13a,b. Compound 13a was converted to the sulfoxide 15 by a sequential diastereoselective reduction of the ketone and an oxidation with mCPBA. Activation of 15 with Tf2O provided the desired cyclized compound 17. In this reaction, the aldol product 13a was also obtained as a consequence of a competitive intramolecular version of DMSO-oxidation via a 7-membered ring intermediate. Compound 18 or 19 are ready for use as a glycosyl donor in glycosylations to provide a range of analogues as potential glycosyltransferase inhibitors as well as related natural products.


Asunto(s)
Antibacterianos/síntesis química , Tunicamicina/análogos & derivados , Uracilo/análogos & derivados , Antibacterianos/química , Frío , Yoduros/química , Samario/química , Tunicamicina/síntesis química , Tunicamicina/química , Uracilo/síntesis química , Uracilo/química
6.
Org Biomol Chem ; 1(21): 3716-25, 2003 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-14649903

RESUMEN

A synthetic approach to the tunicamycins, a complex family of nucleosides with potent antibiotic and antiviral activities is reported based on diazo chemistry. The corresponding precursors for the synthesis of tunicaminyl uracil derivatives, the non-stabilized diazo derived from 13 and the aldehyde derivative of uridine, compound 4, were prepared efficiently from commercially available D-galactal and uridine, respectively. After a high yielding coupling reaction to obtain the ketone 14, a stereoselective reduction provided the corresponding tunicaminyl uracil derivative 17a and its C-7 epimer 17b. The interconversion of the diazo and aldehyde functional groups in the requisite building blocks was similarly achieved to obtain the ketone 32, which after reduction yielded the corresponding 7-deoxy-6-hydroxy tunicaminyl uracil analogs 33a and 33b.


Asunto(s)
Compuestos Azo/química , Tunicamicina/síntesis química , Espectroscopía de Resonancia Magnética , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
7.
Bioorg Med Chem ; 5(4): 661-72, 1997 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-9158864

RESUMEN

The design and synthesis of several beta-1,4-galactosyltransferase inhibitors are reported. Mimics of the pyrophosphate-Mn2+ complex were the focus of the design. Malonic, tartaric, and monosaccharide moieties were used as replacements of the pyrophosphate moiety, and galactose or azasugars with potent galactosidase inhibitory activity were used as the 'donor' component. Compound 6, in which glucose was used as the pyrophosphate-Mn2+ complex mimic and galactose as the 'donor' component, showed the best inhibitory activity towards the transferase with a Ki of 119.6 microM.


Asunto(s)
Aminoglicósidos , Difosfatos/metabolismo , Inhibidores Enzimáticos/síntesis química , Fucosiltransferasas/metabolismo , N-Acetil-Lactosamina Sintasa/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/metabolismo , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/metabolismo , Antivirales/síntesis química , Antivirales/química , Antivirales/metabolismo , Sitios de Unión , Difosfatos/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Malonatos/química , Manganeso/metabolismo , Monosacáridos/química , Nucleósidos de Pirimidina/síntesis química , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/metabolismo , Especificidad por Sustrato , Tartratos/química , Tunicamicina/síntesis química , Tunicamicina/química , Tunicamicina/metabolismo
8.
Carbohydr Res ; 299(4): 245-52, 1997 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-9175272

RESUMEN

The synthesis of the title compounds is described, i.e. coupling of the ylide, generated from the iodophosphonium salt of protected N-phthaloyl-D-galactosamine with 2,3-O-isopropylidene D-ribo-aldehyde afforded an undecose in high yield. Hydroboration-oxidation reaction of the olefinic linkage in the undecose led to the desired tunicamine, as the predominant product. After conversion of the latter to a glycosyl acceptor, this was assembled with the fully protected 2-oxyimino-2-deoxy-alpha-D-arabino-hexopyranosyl bromide, leading to a trehalose-type alpha, beta-disaccharide.


Asunto(s)
Disacáridos/síntesis química , Galactosamina/análogos & derivados , Tunicamicina/análogos & derivados , Tunicamicina/síntesis química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Galactosamina/síntesis química , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Trehalosa/análogos & derivados , Trehalosa/síntesis química , Trisacáridos/síntesis química
9.
Anal Biochem ; 159(1): 210-6, 1986 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-3028211

RESUMEN

A relatively simple and inexpensive procedure was devised for the radiolabeling of the glycoprotein biosynthesis inhibitor, tunicamycin. The procedure is based on hydrogen exchange in alkaline solutions of tritiated water. It was noted that the antibiotic was much more alkali labile than model compounds such as uridine. The alkali stability of the inhibitor was studied to determine conditions for optimum labeling and yield. The effects of alkaline incubation on the inhibitory properties of the antibiotic were also investigated and it was found that the breakdown products are not effective inhibitors of the reaction that transfers N-acetylglucosamine-1-phosphate to dolichyl phosphate. The isolated radioactive tunicamycin homologs, however, retained all their inhibitory action. Incubation of tunicamycin in the presence of deuterated water and mass spectral analysis showed that under the conditions used for the tritiation of tunicamycin the major product exchanged six hydrogen atoms. The position of the tritium atoms in labeled tunicamycin was not determined. The radioactive label in these compounds was shown to be stable under physiological conditions and should be useful for investigations involving the action of these antibiotics.


Asunto(s)
Transferasas (Grupos de Otros Fosfatos Sustitutos) , Tunicamicina/síntesis química , Álcalis , Fosfotransferasas/antagonistas & inhibidores , Radioquímica , Tritio , Tunicamicina/farmacología
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