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1.
Methods Enzymol ; 623: 291-314, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31239051

RESUMEN

RNA targeted high-throughput assays that allow for rapid detection of high affinity binding ligands are important in RNA recognition studies. A number for fluorescent dyes have been reported that can assist in rapidly identifying nucleic acid (RNA) binding elements without the need for immobilization of RNA or the ligand. A number of these dyes are planar aromatic molecules that bind non-specifically to nucleic acids and often distort their parent nucleic acid structures leading to ambiguity in the interpretation of results. In this light, we report here, the use of an aminoglycoside (neomycin) based fluorescent probe (F-Neo) which can reversibly bind to different RNA motifs and help identify ligands with needed affinity and selectivity, without any immobilization of the probe or the target. In this chapter, we provide the details of the assay development, experimental considerations and data analysis to use the probe and identify novel ligands. We then provide a brief introduction to calorimetry (ITC) and circular dichroism (CD) spectroscopy based methods in validating the binding of such identified compounds.


Asunto(s)
Colorantes Fluorescentes/metabolismo , Neomicina/metabolismo , ARN/metabolismo , Espectrometría de Fluorescencia/métodos , Aminoglicósidos/química , Aminoglicósidos/metabolismo , Sitios de Unión , Calorimetría/métodos , Dicroismo Circular/métodos , Descubrimiento de Drogas/métodos , Colorantes Fluorescentes/química , Ligandos , Modelos Moleculares , Neomicina/análogos & derivados , ARN/química
2.
Bioorg Med Chem Lett ; 29(2): 339-341, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30477891

RESUMEN

Synthetic neamine mimetics have been evaluated for binding to the HIV-1 Rev response element. Modified neamine derivatives, obtained from reductive amination of neamine, led to identification of new 6-amino modified neamine-type ligands with HIV-1 RRE binding affinity up to 20× that of neamine and up to 6× that of the more complex neomycin itself. This provides a noteworthy structure-activity increase and a useful lead to simplified, chemically accessible mimetics.


Asunto(s)
Fármacos Anti-VIH/farmacología , Framicetina/farmacología , VIH-1/efectos de los fármacos , Neomicina/farmacología , ARN Viral/efectos de los fármacos , Elementos de Respuesta/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Relación Dosis-Respuesta a Droga , Framicetina/síntesis química , Framicetina/química , Estructura Molecular , Neomicina/análogos & derivados , Neomicina/química , Relación Estructura-Actividad
3.
Anal Chem ; 90(3): 1934-1940, 2018 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-29293308

RESUMEN

Magnetic resonance imaging (MRI) is a powerful diagnostic technique that can penetrate deep into tissue providing excellent spatial resolution without the need for ionizing radiation or harmful radionuclides. However, diagnosing bacterial infections in vivo with clinical MRI is severely hampered by the lack of contrast agents with high relaxivity, targeting capabilities, and bacterial penetration and specificity. Here, we report the development of the first gadolinium (Gd)-based bacteria-specific targeting MRI contrast agent, probe 1, by conjugating neomycin, an aminoglycoside antibiotic, with Dotarem (Gd-DOTA, an FDA approved T1-weighted MRI contrast agent). The T1 relaxivity of probe 1 was found to be comparable to that of Gd-DOTA; additionally, probe 1-treated bacteria generated a significantly brighter T1-weighted MR signal than Gd-DOTA-treated bacteria. More importantly, in vitro cellular studies and preliminary in vivo MRI demonstrated probe 1 exhibits the ability to efficiently target bacteria over macrophage-like cells, indicating its great potential for high-resolution imaging of bacterial infections in vivo.


Asunto(s)
Antibacterianos/química , Infecciones Bacterianas/diagnóstico por imagen , Medios de Contraste/química , Compuestos Heterocíclicos/química , Imagen por Resonancia Magnética/métodos , Neomicina/análogos & derivados , Compuestos Organometálicos/química , Animales , Antibacterianos/síntesis química , Medios de Contraste/síntesis química , Escherichia coli/aislamiento & purificación , Infecciones por Escherichia coli/diagnóstico por imagen , Compuestos Heterocíclicos/síntesis química , Masculino , Ratones , Ratones Endogámicos C57BL , Neomicina/síntesis química , Compuestos Organometálicos/síntesis química , Células RAW 264.7 , Infecciones Estafilocócicas/diagnóstico por imagen , Staphylococcus aureus/aislamiento & purificación
4.
J Am Chem Soc ; 139(41): 14611-14619, 2017 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-28892368

RESUMEN

The preparation of a series of four analogues of the aminoglycoside antibiotics neomycin and paromomycin is described in which ring I, involved in critical binding interactions with the ribosomal target, is replaced by an apramycin-like dioxabicyclo[4.4.0]octane system. The effect of this modification is to lock the hydroxymethyl side chain of the neomycin or paromomycin ring I, as part of the dioxabicyclooctane ring, into either the gauche-gauche or the gauche-trans conformation (respectively, axial or equatorial to the bicyclic system). The antiribosomal activity of these compounds is investigated with cell-free translation assays using both bacterial ribosomes and recombinant hybrid ribosomes carrying eukaryotic decoding A site cassettes. Compounds substituted with an equatorial hydroxyl or amino group in the newly formed ring are considerably more active than their axial diastereomers, lending strong support to crystallographically derived models of aminoglycoside-ribosome interactions. One such bicyclic compound carrying an equatorial hydroxyl group has activity equal to that of the parent yet displays better ribosomal selectivity, predictive of an enhanced therapeutic index. A paromomycin analog lacking the hydroxymethyl ring I side chain is considerably less active than the parent. Antibacterial activity against model Gram negative and Gram positive bacteria is reported for selected compounds, as is activity against ESKAPE pathogens and recombinant bacteria carrying specific resistance determinants. Analogues with a bicyclic ring I carrying equatorial amino or hydroxyl groups mimicking the bound side chains of neomycin and paromomycin, respectively, show excellent activity and, by virtue of their novel structure, retain this activity in strains that are insensitive to the parent compounds.


Asunto(s)
Antibacterianos/química , Antibacterianos/síntesis química , Nebramicina/análogos & derivados , Paromomicina/análogos & derivados , Nebramicina/síntesis química , Nebramicina/química , Neomicina/análogos & derivados , Paromomicina/síntesis química , Ribosomas/metabolismo
5.
ACS Infect Dis ; 3(5): 368-377, 2017 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-28343384

RESUMEN

The synthesis of a series of neomycin derivatives carrying the 2-hydroxyethyl substituent on N6' and/or N6‴ both alone and in combination with a 4'-O-ethyl group is described. By means of cell-free translation assays with wild-type bacterial ribosomes and their hybrids with eukaryotic decoding A sites, we investigate how individual substituents and their combinations affect activity and selectivity at the target level. In principle, and as shown by cell-free translation assays, modifications of the N6' and N6‴ positions allow enhancement of target selectivity without compromising antibacterial activity. As with the 6'OH aminoglycoside paromomycin, the 4'-O-ethyl modification affects the ribosomal activity, selectivity, and antibacterial profile of neomycin and its 6'-N-(2-hydroxyethyl) derivatives. The modified aminoglycosides show good antibacterial activity against model Gram-positive and Gram-negative microbes including the ESKAPE pathogens Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, and Acinetobacter baumannii.


Asunto(s)
Antibacterianos/síntesis química , Neomicina/análogos & derivados , Paromomicina/análogos & derivados , Biosíntesis de Proteínas/efectos de los fármacos , Ribosomas/efectos de los fármacos , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/crecimiento & desarrollo , Antibacterianos/farmacología , Emparejamiento Base , Secuencia de Bases , Conformación de Carbohidratos , Enterobacter cloacae/efectos de los fármacos , Enterobacter cloacae/crecimiento & desarrollo , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana , Neomicina/farmacología , Paromomicina/farmacología , Ribosomas/genética , Ribosomas/metabolismo , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Relación Estructura-Actividad , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/metabolismo
6.
Chem Commun (Camb) ; 53(8): 1366-1369, 2017 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-27935615
7.
Nucleic Acids Res ; 43(17): 8601-13, 2015 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-26264664

RESUMEN

Leishmaniasis comprises an array of diseases caused by pathogenic species of Leishmania, resulting in a spectrum of mild to life-threatening pathologies. Currently available therapies for leishmaniasis include a limited selection of drugs. This coupled with the rather fast emergence of parasite resistance, presents a dire public health concern. Paromomycin (PAR), a broad-spectrum aminoglycoside antibiotic, has been shown in recent years to be highly efficient in treating visceral leishmaniasis (VL)-the life-threatening form of the disease. While much focus has been given to exploration of PAR activities in bacteria, its mechanism of action in Leishmania has received relatively little scrutiny and has yet to be fully deciphered. In the present study we present an X-ray structure of PAR bound to rRNA model mimicking its leishmanial binding target, the ribosomal A-site. We also evaluate PAR inhibitory actions on leishmanial growth and ribosome function, as well as effects on auditory sensory cells, by comparing several structurally related natural and synthetic aminoglycoside derivatives. The results provide insights into the structural elements important for aminoglycoside inhibitory activities and selectivity for leishmanial cytosolic ribosomes, highlighting a novel synthetic derivative, compound 3: , as a prospective therapeutic candidate for the treatment of VL.


Asunto(s)
Antiprotozoarios/química , Leishmania/efectos de los fármacos , Paromomicina/química , Inhibidores de la Síntesis de la Proteína/química , Ribosomas/efectos de los fármacos , Animales , Antiprotozoarios/farmacología , Antiprotozoarios/toxicidad , Sitios de Unión , Línea Celular , Simulación por Computador , Cobayas , Humanos , Leishmania/crecimiento & desarrollo , Macrófagos/parasitología , Masculino , Modelos Moleculares , Neomicina/análogos & derivados , Neomicina/química , Neomicina/toxicidad , Paromomicina/farmacología , Paromomicina/toxicidad , Biosíntesis de Proteínas/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Inhibidores de la Síntesis de la Proteína/toxicidad , ARN Ribosómico/química , Ribosomas/química
8.
Bioorg Med Chem ; 23(13): 3105-9, 2015 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-26025072

RESUMEN

DNA-protein recognition has shown us the importance of DNA shapes in the recognition process. Specific high-affinity targeting of DNA shapes by small molecules is desirable for many biological applications that involve regulation of DNA based processes. Here, the effect of linker length and rigidity on the affinity of a conjugated neomycin dimer for a specific DNA shape (B* form) AT-rich DNA was explored. Binding constants approximating 10(8)M(-1) for optimal linker lengths of 18-19 atoms are reported herein.


Asunto(s)
ADN Forma B/química , Neomicina/química , Secuencia Rica en At , Sitios de Unión , Dimerización , Cinética , Neomicina/análogos & derivados , Relación Estructura-Actividad
9.
Bioorg Med Chem Lett ; 25(4): 815-9, 2015 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-25597008

RESUMEN

RNA interference (RNAi) is a promising tool to regulate gene expression by external double stranded RNAs (dsRNAs) such as siRNAs. As an efficient method to deliver siRNAs to liver cells, we propose a novel strategy using vitamin E (VE)-conjugated neomycin derivatives. With the aim of delivering RNAi-based drugs to liver cells, several tripod-type and prodrug-type neomycin derivatives were synthesized, all of which were thermodynamically stabilized RNA duplexes. The prodrug-type derivative 7 and the tripod-type derivative 10 were delivered to liver cancer cells and successfully induced RNAi activity. These results indicated the potential use of natural aminoglycosides as carriers of RNAi drugs.


Asunto(s)
Neomicina/análogos & derivados , Neomicina/síntesis química , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/química , Vitamina E/análogos & derivados , Vitamina E/síntesis química , Animales , Sistemas de Liberación de Medicamentos/métodos , Humanos , Hígado/metabolismo , Ratones , Neomicina/química , Interferencia de ARN , ARN Bicatenario/administración & dosificación , ARN Bicatenario/química , Vitamina E/química
10.
ACS Comb Sci ; 16(12): 711-20, 2014 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-25330415

RESUMEN

Both multicomponent reactions and diversity oriented synthesis are indispensable tools for the modern medicinal chemist. However, their employment for the synthesis of multivalent glycomimetics has not been exploited so far although the importance that such compounds play in exploring multivalency on glycoside inhibition. Herein, we report the combinatorial synthesis of diversity oriented hetero di- and trivalent glycomimetics through a multicomponent domino process. The process is high yielding and very general, working efficiently with easily accessible sugar starting materials such as glycosylamines, glycosylazides, and glycosylisothiocyanates, having the reactive functional groups tethered either directly to the anomeric carbon, through a suitable linker, or to the primary 6 position of hexoses (or 5 position of pentoses), leading, in the latter case, to glycomimetics with artificial enzymatically stable backbone. The process has been also exploited for the multicomponent synthesis of aminoglycoside (neomycin) conjugates.


Asunto(s)
Biomimética , Glicoconjugados/síntesis química , Neomicina/análogos & derivados , Técnicas Químicas Combinatorias/métodos , Glicoconjugados/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Neomicina/síntesis química , Neomicina/química , Espectrometría de Masa por Ionización de Electrospray
11.
ACS Chem Biol ; 9(9): 2067-73, 2014 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-25019242

RESUMEN

Aminoglycoside antibiotics are pseudosaccharides decorated with ammonium groups that are critical for their potent broad-spectrum antibacterial activity. Despite over three decades of speculation whether or not modulation of pKa is a viable strategy to curtail aminoglycoside kidney toxicity, there is a lack of methods to systematically probe amine-RNA interactions and resultant cytotoxicity trends. This study reports the first series of potent aminoglycoside antibiotics harboring fluorinated N1-hydroxyaminobutyryl acyl (HABA) appendages for which fluorine-RNA contacts are revealed through an X-ray cocrystal structure within the RNA A-site. Cytotoxicity in kidney-derived cells was significantly reduced for the derivative featuring our novel ß,ß-difluoro-HABA group, which masks one net charge by lowering the pKa without compromising antibacterial potency. This novel side-chain assists in evasion of aminoglycoside-modifying enzymes, and it can be easily transferred to impart these properties onto any number of novel analogs.


Asunto(s)
Aminoglicósidos/química , Aminoglicósidos/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Neomicina/análogos & derivados , Aminoglicósidos/toxicidad , Antibacterianos/síntesis química , Antibacterianos/toxicidad , Línea Celular/efectos de los fármacos , Técnicas de Química Sintética , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos/métodos , Farmacorresistencia Bacteriana/efectos de los fármacos , Humanos , Riñón/citología , Riñón/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , ARN/química , ARN/metabolismo , Relación Estructura-Actividad
12.
Mol Pharm ; 10(5): 1964-76, 2013 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-23510087

RESUMEN

A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η(6)-p-cym)RuCl(PPh3)2](+), allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N'-di-Boc-N″-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycin-ruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 ≈ 80 µM), whereas the neamine conjugate (4) was inactive (IC50 ≈ 200 µM). However, the guanidinylated analogue of the neomycin-ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 µM in DU-145 and IC50 = 11.33 µM in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 ≫ 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 µM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 µM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.


Asunto(s)
Antineoplásicos/química , Neomicina/análogos & derivados , Compuestos Organometálicos/química , Rutenio/química , Aminoglicósidos/química , Aminoglicósidos/farmacocinética , Aminoglicósidos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Transporte Biológico Activo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Células MCF-7 , Masculino , Neomicina/farmacocinética , Neomicina/farmacología , Compuestos Organometálicos/farmacocinética , Compuestos Organometálicos/farmacología , ARN Neoplásico/efectos de los fármacos , ARN Neoplásico/metabolismo , Rutenio/farmacocinética , Rutenio/farmacología
13.
Bioorg Med Chem Lett ; 23(6): 1671-5, 2013 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-23414844

RESUMEN

Aminoglycoside represents a class of versatile and broad spectrum antibacterial agents. In an effort to revive the antibacterial activity against aminoglycoside resistant bacteria, our laboratory has developed two new classes of aminoglycoside, pyranmycin and amphiphilic neomycin (NEOF004). The former resembles the traditional aminoglycoside, neomycin. The latter, albeit derived from neomycin, appears to exert antibacterial action via a different mode of action. In order to discern that these aminoglycoside derivatives have distinct antibacterial mode of action, RNA-binding affinity and fluorogenic dye were employed. These studies, together with our previous investigation, confirm that pyranmycin exhibit the traditional antibacterial mode of action of aminoglycosides by binding toward the bacterial rRNA. On the other hand, the amphiphilic neomycin, NEOF004 disrupts the bacterial cell wall. In a broader perspective, it verifies that structurally modified neomycin can exert different antibacterial mode of action leading to the revival of activity against aminoglycoside resistant bacteria.


Asunto(s)
Aminoglicósidos/química , Antibacterianos/química , Neomicina/análogos & derivados , Aminoglicósidos/metabolismo , Aminoglicósidos/farmacología , Antibacterianos/metabolismo , Antibacterianos/farmacología , Escherichia coli/efectos de los fármacos , Colorantes Fluorescentes/química , Pruebas de Sensibilidad Microbiana , Neomicina/química , Neomicina/metabolismo , Neomicina/farmacología , Unión Proteica , ARN Ribosómico/química , ARN Ribosómico/metabolismo , Staphylococcus aureus/efectos de los fármacos
14.
Folia Microbiol (Praha) ; 56(6): 555-61, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22083789

RESUMEN

Neomycin, produced by Streptomyces fradiae, has been widely used for the treatment of bacterial infections in clinical and agricultural applications. In this study, a neomycin nonproducing mutant of S. fradiae was obtained by gene disruption technique for mutational biosynthesis. A crucial gene neoC (neo7) which encodes 2-deoxystreptamine (2-DOS) synthases was disrupted. The mutant could resume producing neomycin in the presence of 2-DOS. Salen derivatives of 2-DOS were synthesized and individually added to cultures of the mutant. Antibacterial activity of the mutasynthesis products against Staphylococcus aureus and four plant pathogenic bacteria (Pseudomonas solanacarum, Erwinia carotovora, Xanthomonas oryzae, and Xanthomonas campestris) was detected quantitatively by Oxford cup method. It is suggested that all 2-DOS derivatives were incorporated by the mutant into new active neomycin analogs except for 2-DOS derivative 2d ((1R,2r,3S,4R,6S)-4,6-bis((E)-3,5-di-tert-butyl-2-hydroxybenzylideneamino)cyclohexane-1,2,3-triol). Neomycin analogs produced by feeding 2-DOS derivative 2a ((1R,2r,3S,4R,6S)-4,6-bis((E)-2 hydroxybenzylideneamino)cyclohexane-1,2,3-triol) to cultures of the mutant displayed a similar antibacterial activity with neomycin produced by wild strain.


Asunto(s)
Antibacterianos/biosíntesis , Neomicina/biosíntesis , Streptomyces/genética , Streptomyces/metabolismo , Antibacterianos/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Estructura Molecular , Mutación , Neomicina/análogos & derivados , Streptomyces/enzimología
15.
Carbohydr Res ; 346(17): 2792-800, 2011 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-22015170

RESUMEN

Synthesis of amphiphilic oligosaccharides is problematic because traditional methods for separating and purifying oligosaccharides, including sulfated oligosaccharides, are generally not applicable to working with amphiphilic sugars. We report here RPIP-LC and LC-MS methods that enable the synthesis, separation, and characterization of amphiphilic N-arylacyl O-sulfonated aminoglycosides, which are being pursued as small-molecule glycosaminoglycan mimics. The methods described in this work for separating and characterizing these amphiphilic saccharides are further applied to a number of uses: monitoring the progression of sulfonation reactions with analytical RP-HPLC, characterizing sulfate content for individual molecules with ESI-MS, determining the degree of sulfation for products having mixed degrees of sulfation with HPLC and LC-MS, and purifying products with benchtop C18 column chromatography. We believe that the methods described here will be broadly applicable to enabling the synthesis, separation, and characterization of amphiphilic, sulfated, and phosphorylated oligosaccharides and other types of molecules substituted to varying degrees with both anionic and hydrophobic groups.


Asunto(s)
Kanamicina/análogos & derivados , Neomicina/análogos & derivados , Ésteres del Ácido Sulfúrico/síntesis química , Cromatografía Líquida de Alta Presión , Cromatografía de Fase Inversa , Kanamicina/síntesis química , Kanamicina/aislamiento & purificación , Nebramicina/análogos & derivados , Neomicina/síntesis química , Neomicina/aislamiento & purificación , Espectrometría de Masa por Ionización de Electrospray , Ésteres del Ácido Sulfúrico/química , Ésteres del Ácido Sulfúrico/aislamiento & purificación
16.
Rapid Commun Mass Spectrom ; 24(10): 1439-46, 2010 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-20411583

RESUMEN

Structural elucidation of six regioisomers of mono-N-octyl derivatized neomycin is achieved using MS(n) (up to n = 4) on an ion trap time-of-flight (IT-TOF) instrument equipped with electrospray ionization. The mixture of six derivatized neomycin analogues was generated by reductive amination in a shotgun synthetic approach. In parallel to the liquid chromatography/mass spectrometry (LC/MS) detection, the antibacterial activity of the neomycin regioisomers was tested by post-column addition of buffer and bacterial inocula, subsequent microfractionation of the resulting mixture, incubation, and finally a chemiluminescence-based bioactivity measurement based on the production of bacterial ATP. The MS-based high-resolution screening approach described can be applied in medicinal chemistry to help in designing and producing new antibiotic substances, which is particularly challenging due to the high functionality of most antibiotic substances, therefore requiring advanced (hyphenated) separation and detection techniques for compound mixtures.


Asunto(s)
Bioensayo/métodos , Cromatografía Liquida/métodos , Espectrometría de Masas/métodos , Neomicina/análogos & derivados , Adenosina Trifosfato/metabolismo , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana/métodos , Neomicina/química , Neomicina/metabolismo , Neomicina/farmacología , Estereoisomerismo
17.
J Antibiot (Tokyo) ; 62(10): 539-44, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19629142

RESUMEN

A library of 5''-modified neomycin derivatives were synthesized for an antibacterial structure-activity optimization strategy. Two leads exhibited prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Antibacterial activities were measured when combined with other clinically used antibiotics. Significant synergistic activities were observed, which may lead to the development of novel therapeutic practices in the battle against infectious bacteria.


Asunto(s)
Antibacterianos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Neomicina , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Sinergismo Farmacológico , Quimioterapia Combinada , Enterococcus/efectos de los fármacos , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Neomicina/análogos & derivados , Neomicina/síntesis química , Neomicina/química , Neomicina/farmacología , Relación Estructura-Actividad , Resistencia a la Vancomicina
18.
Electrophoresis ; 30(16): 2869-73, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19637217

RESUMEN

In this paper, a new ligand-exchange -MEKC mode, based on the design of a unique lipohilic species (4'-octadecylneamine derivative), which served both as micelle-forming surfactant (by its hydrophobic part) and central ion-complexing ligand (by its hydrophilic part) is described. The CMC of the used lipophilic neamine derivative was first determined by surface tension measurements. Subsequent NMR experiments were performed in order to investigate the Cu(II) binding properties of the neamine micellar phase. The enantioseparation properties of both the octadecylneamine derivative-Cu(II) MEKC and the native neamine-Cu(II) CE systems were evaluated and compared using the tryptophan racemate as a probe analyte. The effects of several different electrophoretic conditions on the enantiomer migration behavior in the ligand-exchange-MEKC mode were examined. The developed methodology was also applied to the enantioseparation of other analytes such as 1-methyl-tryptophan, 3,5-diiodo-tyrosine and 1-naphtyl-alanine.


Asunto(s)
Cromatografía Capilar Electrocinética Micelar/métodos , Quelantes , Cobre , Ligandos , Metanol/química , Micelas , Neomicina/análogos & derivados , Resonancia Magnética Nuclear Biomolecular , Estereoisomerismo , Tensión Superficial , Tensoactivos/química , Triptófano/análogos & derivados , Triptófano/química
19.
J Mol Model ; 15(3): 281-94, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19057930

RESUMEN

Aminoglycoside-arginine conjugates (AAC and APAC) are multi-target inhibitors of human immunodeficiency virus type-1 (HIV-1). Here, we predict new conjugates of neomycin with two arginine peptide chains binding at specific sites on neomycin [poly-arginine-neomycin-poly-arginine (PA-Neo-PA)]. The rationale for the design of such compounds is to separate two short arginine peptides with neomycin, which may extend the binding region of the CXC chemokine receptor type 4 (CXCR4). We used homology models of CXCR4 and unliganded envelope glycoprotein 120 (HIV-1(IIIB) gp120) and docked PA-Neo-PAs and APACs to these using a multistep docking procedure. The results indicate that PA-Neo-PAs spread over two negatively charged patches of CXCR4. PA-Neo-PA-CXCR4 complexes are energetically more favorable than AACs/APAC-CXCR4 complexes. Notably, our CXCR4 model and docking procedure can be applied to predict new compounds that are either inhibitors of gp120-CXCR4 binding without affecting stromal cell-derived factor 1 alpha (SDF-1 alpha) chemotaxis activity, or inhibitors of SDF-1 alpha-CXCR4 binding resulting in an anti-metastasis effect. We also predict that PA-Neo-PAs and APACs can interfere with CD4-gp120 binding in unliganded conformation.


Asunto(s)
Fármacos Anti-VIH/química , Arginina/química , VIH-1/efectos de los fármacos , Neomicina/análogos & derivados , Oligopéptidos/química , Péptidos/química , Aminoglicósidos/química , Fármacos Anti-VIH/metabolismo , Arginina/metabolismo , Simulación por Computador , Diseño de Fármacos , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/metabolismo , Humanos , Ligandos , Modelos Moleculares , Neomicina/química , Neomicina/metabolismo , Oligopéptidos/metabolismo , Péptidos/metabolismo , Inhibidores de la Síntesis de la Proteína/química , Inhibidores de la Síntesis de la Proteína/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/química , Receptores CXCR4/metabolismo , Electricidad Estática
20.
Biochim Biophys Acta ; 1780(6): 914-20, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18410746

RESUMEN

Aminoglycoside-arginine conjugates (AACs) are multi-target HIV-1 inhibitors. The most potent AAC is neomycin hexa-arginine conjugate, NeoR6. We here demonstrate that NeoR6 interacts with CXCR4 without affecting CXCL12-CXCR4 ordinary chemotaxis activity or loss of CXCR4 cell surface expression. Importantly, NeoR6 alone does not affect cell migration, indicating that NeoR6 interacts with CXCR4 at a distinct site that is important for HIV-1 entry and mAb 12G5 binding, but not to CXCL12 binding or signaling sites. This is further supported by our modeling studies, showing that NeoR6 and CXCL12 bind to two distinct sites on CXCR4, in contrast with other CXCR4 inhibitors, e.g. T140 and AMD3100. This complementary utilization of chemical, biology, and computation analysis provides a powerful approach for designing anti-HIV-1 drugs without interfering with the natural function of CXCL12/CXCR4 binding.


Asunto(s)
Aminoglicósidos/farmacología , Fármacos Anti-VIH/farmacología , Arginina/análogos & derivados , Quimiocina CXCL12/metabolismo , Quimiotaxis/efectos de los fármacos , VIH-1/metabolismo , Neomicina/análogos & derivados , Receptores CXCR4/metabolismo , Aminoglicósidos/química , Fármacos Anti-VIH/química , Anticuerpos Monoclonales/farmacología , Arginina/química , Arginina/farmacología , Bencilaminas , Línea Celular Tumoral , Ciclamas , Regulación de la Expresión Génica/efectos de los fármacos , Compuestos Heterocíclicos/farmacología , Humanos , Neomicina/química , Neomicina/farmacología , Oligopéptidos/farmacología , Unión Proteica/efectos de los fármacos , Receptores CXCR4/antagonistas & inhibidores
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