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1.
J Am Chem Soc ; 142(1): 530-544, 2020 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-31790244

RESUMEN

Apramycin is a structurally unique member of the 2-deoxystreptamine class of aminoglycoside antibiotics characterized by a monosubstituted 2-deoxystreptamine ring that carries an unusual bicyclic eight-carbon dialdose moiety. Because of its unusual structure, apramycin is not susceptible to the most prevalent mechanisms of aminoglycoside resistance including the aminoglycoside-modifying enzymes and the ribosomal methyltransferases whose widespread presence severely compromises all aminoglycosides in current clinical practice. These attributes coupled with minimal ototoxocity in animal models combine to make apramycin an excellent starting point for the development of next-generation aminoglycoside antibiotics for the treatment of multidrug-resistant bacterial infections, particularly the ESKAPE pathogens. With this in mind, we describe the design, synthesis, and evaluation of three series of apramycin derivatives, all functionalized at the 5-position, with the goals of increasing the antibacterial potency without sacrificing selectivity between bacterial and eukaryotic ribosomes and of overcoming the rare aminoglycoside acetyltransferase (3)-IV class of aminoglycoside-modifying enzymes that constitutes the only documented mechanism of antimicrobial resistance to apramycin. We show that several apramycin-5-O-ß-d-ribofuranosides, 5-O-ß-d-eryrthofuranosides, and even simple 5-O-aminoalkyl ethers are effective in this respect through the use of cell-free translation assays with wild-type bacterial and humanized bacterial ribosomes and of extensive antibacterial assays with wild-type and resistant Gram negative bacteria carrying either single or multiple resistance determinants. Ex vivo studies with mouse cochlear explants confirm the low levels of ototoxicity predicted on the basis of selectivity at the target level, while the mouse thigh infection model was used to demonstrate the superiority of an apramycin-5-O-glycoside in reducing the bacterial burden in vivo.


Asunto(s)
Aminoaciltransferasas/metabolismo , Antibacterianos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Glicósidos/química , Nebramicina/análogos & derivados , Antibacterianos/química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Éteres/química , Pruebas de Sensibilidad Microbiana , Nebramicina/química , Nebramicina/farmacología
2.
Chemistry ; 22(51): 18383-18387, 2016 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-27768237

RESUMEN

A "Prins pinacol type rearrangement followed by C4-OBn participation" in a cascade manner has been observed while probing the fate of carbocation in some carbohydrate derived homoallylic alcohols in the Prins reaction. This has led to an easy access to tetrahydrofuran-fused bridged bicyclic ketals (or tetrahydrofuran-fused 1,6-anhydro-heptopyranose frameworks) which are further converted into some annulated sugars and C2-branched heptoses.


Asunto(s)
Carbohidratos/síntesis química , Furanos/síntesis química , Heptosas/síntesis química , Compuestos Policíclicos/síntesis química , Carbohidratos/química , Furanos/química , Heptosas/química , Estructura Molecular , Compuestos Policíclicos/química , Estereoisomerismo
3.
J Org Chem ; 79(4): 1690-9, 2014 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-24456236

RESUMEN

A few bicyclic hybrid sugar molecules comprising of oxa-aza, oxa-oxa, and oxa-carbasugar fused skeletons were designed and synthesized from C-2 acetoxyglucal involving Ferrier rearrangement, Grignard addition, and ring-closing metathesis as key steps. The inhibitory activities of the synthesized molecules were tested against commercially available enzymes, which revealed the sugar-piperidine and sugar-pyran hybrids as potent and selective inhibitors.


Asunto(s)
Compuestos Aza/química , Compuestos Aza/farmacología , Carba-azúcares/química , Carba-azúcares/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Glicósido Hidrolasas/antagonistas & inhibidores , Glicósido Hidrolasas/química , Óxidos/química , Óxidos/farmacología , Piperidinas/química , Piranos/química
4.
ACS Infect Dis ; 9(8): 1622-1633, 2023 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-37481733

RESUMEN

Complementing our earlier syntheses of the gentamicins B1, C1a, C2b, and X2, we describe the synthesis of gentamicins C1, C2, and C2a characterized by methyl substitution at the 6'-position, and so present an alternative access to previous chromatographic methods for accessing these sought-after compounds. We describe the antiribosomal activity of our full set of synthetic gentamicin congeners against bacterial ribosomes and hybrid ribosomes carrying the decoding A site of the human mitochondrial, A1555G mutant mitochondrial, and cytoplasmic ribosomes and establish structure-activity relationships with the substitution pattern around ring I to antiribosomal activity, antibacterial resistance due to the presence of aminoglycoside acetyl transferases acting on the 6'-position in ring I, and literature cochlear toxicity data.


Asunto(s)
Antibacterianos , Gentamicinas , Humanos , Gentamicinas/farmacología , Gentamicinas/análisis , Antibacterianos/farmacología , Antibacterianos/química , Aminoglicósidos
5.
Carbohydr Res ; 500: 108254, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33561715

RESUMEN

We describe the preparation of methyl 5α-methyl-α-d-glucopyranoside and of 5α-fluoro-ß-d-glucopyranose per acetate and the NMR-based conformational analysis of their side chains. Both the 5α-methyl and 5α-fluoro substituents increase the population of the gauche,gauche side chain conformer to the extent that it becomes the predominant conformation. In the 5α-methyl series this is attributed to steric effects, whereas in the 5α-fluoro series the optimization of attractive gauche effects is the more likely reason.


Asunto(s)
Glucósidos/química , Pironas/química , Conformación de Carbohidratos , Glucósidos/síntesis química , Pironas/síntesis química
6.
Org Lett ; 22(10): 3850-3854, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32343899

RESUMEN

The clinical aminoglycoside antibiotic gentamicin is a mixture of several difficult-to-separate major and minor components. The relative inaccessibility of the minor components in particular complicates efforts to separate antibacterial activity from nephro- and/or ototoxicity and to clarify the origin of the potentially therapeutically important read-through activity. With a view to facilitating such studies, the synthesis of a fully and selectively protected garamine-based acceptor has been developed from readily available sisomicin. Glycosylation of this acceptor with a 6-azido-6,7-dideoxy-d-glycero-d-glucoheptopyranosyl donor affords gentamicin B1 after deprotection, whereas employment of a 2-azido-2-deoxy-d-glucopyranosyl donor under N,N-dimethylformamide-directed glycosylation conditions affords gentamicin X2 after deprotection.


Asunto(s)
Aminoglicósidos/química , Antibacterianos/síntesis química , Disacáridos/química , Gentamicinas/química , Antibacterianos/química , Gentamicinas/síntesis química , Gentamicinas/farmacología , Glicosilación , Humanos , Estructura Molecular
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