RESUMEN
A diverse series of 43 novel "soft antimicrobials" based on quaternary ammonium pyridoxine derivatives which include six-membered acetals and ketals of pyridoxine bound via cleavable linker moieties (amide, ester) with a fragment of fatty carboxylic acid was designed. Nine compounds exhibited in vitro promising antibacterial activity against Gram-positive and Gram-negative bacterial strains with MIC values comparable with reference antiseptics miramistin, benzalkonium chloride and chlorohexidine. On various clinical isolates, the lead compounds 6i and 12a exhibited antibacterial activity comparable with that of benzalkonium chloride while higher than that of miramistin. Moreover, 6i and 12a were able to kill bacteria embedded into the matrix of mono- and dual species biofilms. The treatment of bacterial cells by either 6i and 12a lead to fast depolarization of the membrane suggesting that the membrane is an apparent molecular target of compounds. 6i and 12a were non mutagenic neither in SOS-chromotest nor in Ames test and non-toxic in vivo at acute oral (LD50 > 2000 mg/kg) and cutaneous administration (LD50 > 2500 mg/kg) on mice. Taken together, our data allow suggesting described active compounds as promising starting point for the new antibacterial agents development.
Asunto(s)
Antibacterianos/química , Antibacterianos/síntesis química , Ácidos Grasos/síntesis química , Piridoxina/síntesis química , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/síntesis química , Humanos , Estructura MolecularRESUMEN
Many pathogenic bacteria and microscopic fungi form rigid polymicrobial biofilms this way enhancing their resistant to treatment. A series of novel pyridoxine-based quaternary ammonium derivatives of terbinafine characterized by both antifungal and antibacterial activities was designed. The leading compound named KFU-127 exhibits promising antifungal and antibacterial activities against various bacteria and micromycetes in both planktonic and biofilm-embedded forms demonstrating MIC values comparable with those of conventional antifungals and antimicrobials. Similar to other antiseptics like benzalkonium chloride and miramistin, KFU-127 is considerably toxic for eukaryotic cells that limits is application to topical treatment options. On the other hand, KFU-127 reduces the number of viable biofilm-embedded bacteria and C. albicans by 3 orders of magnitude at concentrations 2-4 times lower than those of reference drugs and successfully eradicates S. aureus-C. albicans mixed biofilms. The mechanism of antimicrobial action of KFU-127 is bimodal including both membrane integrity damage and pyridoxal-dependent enzymes targeting. We expect that this bilateral mechanism would result in lower rates of resistance development in both fungal and bacterial pathogens. Taken together, our data suggest KFU-127 as a new promising broad spectrum topical antimicrobial capable of one-shot targeting of bacterial and fungal-bacterial biofilms.
Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Biopelículas/efectos de los fármacos , Piridoxina/farmacología , Compuestos de Amonio Cuaternario/farmacología , Terbinafina/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Bacterias/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Hongos/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piridoxina/síntesis química , Piridoxina/química , Compuestos de Amonio Cuaternario/síntesis química , Compuestos de Amonio Cuaternario/química , Relación Estructura-Actividad , Terbinafina/síntesis química , Terbinafina/químicaRESUMEN
A series of 108 novel quaternary bis-ammonium pyridoxine derivatives carrying various substituents at the quaternary nitrogen's and acetal carbon was synthesized. Thirteen compounds exhibited antibacterial and antifungal activity (minimum inhibitory concentration (MIC) 0.25-16 µg/mL) comparable or superior than miramistin, benzalkonium chloride, and chlorhexidine. A strong correlation between the lipophilicity and antibacterial activity was found. The most active compounds had logP values in the range of 1-3, while compounds with logP > 6 and logP < 0 were almost inactive. All active compounds demonstrated cytotoxicity comparable with miramistin and chlorhexidine on HEK-293 cells and were three-fold less toxic when compared to benzalkonium chloride. The antibacterial activity of leading compound 5c12 on biofilm-embedded Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli or Pseudomonas aeruginosa was comparable or even higher than that of the benzalkonium chloride. In vivo 5c12was considerably less toxic (LD50 1705 mg/kg) than benzalkonium chloride, miramistine, and chlorhexidine at oral administration on CD-1 mice. An aqueous solution of 5c12 (0.2%) was shown to be comparable to reference drugs efficiency on the rat's skin model. The molecular target of 5c12 seems to be a cellular membrane as other quaternary ammonium salts. The obtained results make the described quaternary bis-ammonium pyridoxine derivatives promising and lead molecules in the development of the new antiseptics with a broad spectrum of antimicrobial activity.
Asunto(s)
Compuestos de Amonio/química , Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Piridoxina/síntesis química , Piridoxina/farmacología , Sales (Química)/química , Antiinfecciosos/química , Antiinfecciosos/toxicidad , Biopelículas/efectos de los fármacos , Técnicas de Química Sintética , Células HEK293 , Humanos , Pruebas de Sensibilidad Microbiana , Piridoxina/química , Piridoxina/toxicidad , Relación Estructura-ActividadRESUMEN
The pyridine-derived biomolecules are of considerable interest in developing medicinal compounds with various specific activities. Novel ammonium salts of pyridoxine, (S)-(-)-nicotine and nicotinamide with O,O-diorganyl dithiophosphoric acids (DTPA) were synthesized and characterized. The complexation of chiral monoterpenyl DTPA, including (S)-(-)-menthyl, (R)-(+)-menthyl, (1R)-endo-(+)-fenchyl, (1S,2S,3S,5R)-(+)-isopinocampheolyl derivatives, with pyridoxine and nicotine provided effective antibacterial compounds 3a,b,e,f, and 5a,b,d,f with MIC values against Gram-positive bacteria as low as 10⯵M (6⯵g/mL). Two selected pyridoxine and nicotine salts based on menthyl DTPA 3a and 5a were similarly active against antibiotic-resistant bacteria from burn wounds including MRSA. The compounds had enhanced amphiphilic and hemolytic properties and effectively altered surface characteristics and matrix-secreting ability of P. aeroginosa and S. aureus. MBC/MIC ratios of 3a and 5a suggested the bactericidal mode of their action. Furthermore, the compounds exhibited moderate cytotoxicity towards human skin fibroblasts (IC50â¯=â¯48.6 and 57.6⯵M, respectively, 72â¯h), encouraging their further investigation as potential antimicrobials against skin and wound infections.
Asunto(s)
Antibacterianos/farmacología , Niacinamida/farmacología , Nicotina/farmacología , Fosfatos/farmacología , Piridoxina/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/toxicidad , Fibroblastos/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Hemólisis/efectos de los fármacos , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Niacinamida/síntesis química , Niacinamida/química , Niacinamida/toxicidad , Nicotina/síntesis química , Nicotina/química , Nicotina/toxicidad , Fosfatos/síntesis química , Fosfatos/química , Fosfatos/toxicidad , Piridoxina/síntesis química , Piridoxina/química , Piridoxina/toxicidad , Staphylococcus epidermidis/efectos de los fármacosRESUMEN
Two series of novel pyridoxine-based azaheterocyclic analogs of feruloyl methane (Dehydrozingerone, DZG) were synthesized, and their biological activity against a panel of tumor and normal cell lines was evaluated in vitro. The most active compounds possessed expressed cytotoxic activity, which was comparable to cytotoxic activity of doxorubicin and significantly higher than that of DZG, and a remarkable selectivity for the studied cancer cell lines as compared to the normal cells. The leading compound and DZG initiated arrest of the cell cycle in the G2/M phase, preventing normal division and further transition of daughter cells to the G0/G1 phase. Similar to DZG, but with higher efficiency, the leading compound was able to inhibit migration activity and, therefore, invasiveness of tumor cells. It also increased concentration of reactive oxygen species in tumor cells, induced depolarization of mitochondrial membranes and initiated apoptosis accompanied by disruption of integrity of cytoplasmic cell membranes. By contrast to DZG, the leading compound did not possess antioxidant properties. The obtained data make the described chemotype a promising starting point for the development of new anticancer agents.
Asunto(s)
Alquenos/farmacología , Antineoplásicos/farmacología , Metano/farmacología , Piridoxina/farmacología , Alquenos/síntesis química , Alquenos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Metano/análogos & derivados , Modelos Moleculares , Estructura Molecular , Piridoxina/síntesis química , Piridoxina/química , Relación Estructura-ActividadRESUMEN
Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are now considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus. In this work, a series of novel symmetric molecular constructs, in which two pyridoxine moieties are connected via sulfur-containing linkers, have been synthesized and tested in vitro for glucokinase activation potential. The enzyme activation rates by two most active compounds at 100 µM (~150% and 130%) were comparable to that of the reference agent PF-04937319 (~154%). Both leading compounds demonstrated low cytotoxicity and excellent safety profile in acute toxicity experiment in rats after oral administration with LD50 exceeding 2000 mg/kg of body weight. Binding mode of the active compounds in comparison with the reference agent was studied using molecular docking. The leading compounds represent viable preclinical candidates for the treatment of type 2 diabetes mellitus, as well as a promising starting point for the design of structural analogs with improved activity.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Activadores de Enzimas/uso terapéutico , Glucoquinasa/metabolismo , Piridoxina/uso terapéutico , Sitio Alostérico , Animales , Activadores de Enzimas/síntesis química , Activadores de Enzimas/química , Femenino , Humanos , Masculino , Simulación del Acoplamiento Molecular , Piridoxina/síntesis química , Piridoxina/química , Ratas , Pruebas de Toxicidad AgudaRESUMEN
A series of novel quaternary ammonium 4-deoxypyridoxine derivatives was synthesized. Two compounds demonstrated excellent activity against a panel of Gram-positive methicillin-resistant S. aureus strains with MICs in the range of 0.5-2 µg/mL, exceeding the activity of miramistin. At the same time, both compounds were inactive against the Gram-negative E. coli and P. aeruginosa strains. Cytotoxicity studies on human skin fibroblasts and embryonic kidney cells demonstrated that the active compounds possessed similar toxicity with benzalkonium chloride but were slightly more toxic than miramistin. SOS-chromotest in S. typhimurium showed the lack of DNA-damage activity of both compounds; meanwhile, one compound showed some mutagenic potential in the Ames test. The obtained results make the described chemotype a promising starting point for the development of new antibacterial therapies.
Asunto(s)
Antibacterianos/administración & dosificación , Antibacterianos/síntesis química , Fenómenos Fisiológicos Bacterianos/efectos de los fármacos , Piridoxina/análogos & derivados , Compuestos de Amonio Cuaternario/administración & dosificación , Antibacterianos/toxicidad , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Piridoxina/administración & dosificación , Piridoxina/síntesis química , Piridoxina/química , Piridoxina/toxicidad , Compuestos de Amonio Cuaternario/síntesis química , Compuestos de Amonio Cuaternario/toxicidadRESUMEN
A series of 26 quaternary ammonium pyridoxine derivatives were synthesized and their cytotoxicity and antibacterial activities against clinically relevant bacterial strains were tested in vitro. The antibacterial activity of mono-ammonium salts increased with the rise of the lipophilicity and compound 3,3,5-trimethyl-8,8-dioctyl-1,7,8,9-tetrahydro-[1,3]dioxino[5,4-d]pyrrolo[3,4-b]pyridin-8-ium chloride (2d) reaches a maximum among them. Bis-ammonium salt of pyridoxine 4 with two dimethyloctylamine groups also demonstrated high antibacterial activity despite lower lipophilicity. The results of MTT assay indicated that HEK 293 cells were more sensitive than HSF to quaternary ammonium pyridoxine derivatives. Compounds 2d and 4 did not induce the damage of the DNA and might be of interest in the development of new antimicrobials.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Piridoxina/síntesis química , Piridoxina/farmacología , Compuestos de Amonio Cuaternario/química , Antibacterianos/química , Antibacterianos/toxicidad , Bacterias/efectos de los fármacos , Técnicas de Química Sintética , Interacciones Hidrofóbicas e Hidrofílicas , Pruebas de Sensibilidad Microbiana , Pruebas de Mutagenicidad , Piridoxina/química , Piridoxina/toxicidadRESUMEN
A series of 13 phosphonium salts on the basis of pyridoxine derivatives were synthesized and their antibacterial activity against clinically relevant strains was tested in vitro. All compounds were almost inactive against gram-negative bacteria and exhibited structure-dependent activity against gram-positive bacteria. A crucial role of ketal protection group in phosphonium salts for their antibacterial properties was demonstrated. Among synthesized compounds 5,6-bis[triphenylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (compound 20) was found to be the most effective towards Staphylococcus aureus and Staphylococcus epidermidis strains (MIC 5µg/ml). The mechanism of antibacterial activity of this compound probably involves cell penetration and interaction with genomic and plasmid DNA.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Compuestos Organofosforados/síntesis química , Compuestos Organofosforados/farmacología , Células Cultivadas , Fibroblastos/efectos de los fármacos , Humanos , Estructura Molecular , Compuestos Organofosforados/química , Piridoxina/síntesis química , Piridoxina/química , Piridoxina/farmacología , Piel/efectos de los fármacosRESUMEN
The discovery of vitamins as essential factors in the diet was a scientific breakthrough that changed the world. Diseases such as scurvy, rickets, beriberi, and pellagra were recognized to be curable with an adequate diet. These diseases had been prevalent for thousands of years and had a dramatic impact on societies as well as on economic development. This Review highlights the key achievements in the development of industrial processes for the manufacture of eight of the 13 vitamins.
Asunto(s)
Disciplinas de las Ciencias Naturales/historia , Vitaminas/historia , Ácido Ascórbico/síntesis química , Ácido Ascórbico/historia , Ácido Ascórbico/metabolismo , Biotina/síntesis química , Biotina/historia , Biotina/metabolismo , Historia del Siglo XX , Humanos , Ácido Pantoténico/síntesis química , Ácido Pantoténico/historia , Ácido Pantoténico/metabolismo , Piridoxina/síntesis química , Piridoxina/historia , Piridoxina/metabolismo , Riboflavina/síntesis química , Riboflavina/historia , Riboflavina/metabolismo , Tiamina/síntesis química , Tiamina/historia , Tiamina/metabolismo , Vitamina A/síntesis química , Vitamina A/historia , Vitamina A/metabolismo , Vitamina E/síntesis química , Vitamina E/historia , Vitamina E/metabolismo , Vitaminas/síntesis química , Vitaminas/metabolismoRESUMEN
pH plays an important role in tumor proliferation, angiogenesis, metabolic control, and the efficacy of cytotoxic therapy, and accurate noninvasive assessment of tumor pH promises to provide insight into developmental processes and prognostic information. In this paper, we report the design, synthesis, and characterization of two novel pH indicators 6-trifluoromethylpyridoxine 8 and α(4),α(5)-di-O-[3'-O-(ß-d-glucopyranosyl)propyl]-6-trifluoromethylpyridoxine 17 and demonstrate 8 as an extracellular (19)F NMR pH probe to assess pH(e) of various tumors in vivo.
Asunto(s)
Indicadores y Reactivos/síntesis química , Piridoxina/análogos & derivados , Animales , Espacio Extracelular/química , Femenino , Flúor , Concentración de Iones de Hidrógeno , Indicadores y Reactivos/química , Espectroscopía de Resonancia Magnética/métodos , Masculino , Miocardio/química , Neoplasias Experimentales/química , Piridoxina/síntesis química , Piridoxina/química , Ratas , Ratas Endogámicas F344 , Microambiente TumoralRESUMEN
Enzymatic syntheses of pyridoxine glycosides were carried out in di-isopropyl ether organic medium using beta-glucosidase isolated from sweet almond. Optimum conditions determined for the reaction with D-glucose were 40% (w/w D-glucose) beta-glucosidase at 0.18 mM (1.8 ml) of pH 5 acetate buffer over a 72 h incubation period. Of 11 carbohydrates employed, beta-glucosidase gave 7-O-(alpha-D-glucopyranosyl)pyridoxine 5a, 7-O-(beta-D-glucopyranosyl)pyridoxine 5b, 6-O-(alpha-D-glucopyranosyl)pyridoxine 5c, 7-O-(alpha-D-galactopyranosyl)pyridoxine 6a, 7-O-(beta-D-galactopyranosyl)pyridoxine 6b, 6-O-(alpha-D-galactopyranosyl)pyridoxine 6c, 7-O-(alpha-D-mannopyranosyl)pyridoxine 7a, 7-O-(beta-D-mannopyranosyl)pyridoxine 7b, and 6-O-(alpha-D-mannopyranosyl)pyridoxine 7c in yields ranging from 23 to 40%.
Asunto(s)
Glicósidos/síntesis química , Piridoxina/síntesis química , beta-Glucosidasa/metabolismo , Carbohidratos , Glicósidos/análisis , Prunus/enzimología , Piridoxina/análisis , SolventesRESUMEN
The new tetra dentate dianionic H2PS (N,N'-dipyridoxyl (1,3-propylenediamine)) Schiff-base ligand and its octahedral Co(III) salen complex [Co(PS)(H2O)(CH3OH)]+CH3COO(-) were synthesized, where coordinating atoms of H2PS (N,N,O(-),O(-)) occupied equatorial positions with H2O and CH3OH as axial ligands. The nature of the H2PS and its complex were determined by elemental and spectrochemical (IR, UV-vis, 1H NMR and Mass) analysis. Also, the fully optimized geometries and vibrational frequencies of them together with the 1H NMR chemical shifts of H2PS have been calculated using density functional theory (B3LYP) method. Obtained structural parameters are in good agreement with the experimental data reported for similar compounds. The calculated and experimental results confirmed the suggested structures for the ligand and complex.
Asunto(s)
Cobalto/química , Diaminas/química , Diaminas/síntesis química , Piridoxina/análogos & derivados , Bases de Schiff/síntesis química , Técnicas de Química Analítica/métodos , Ligandos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas/métodos , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Piridinas/química , Piridoxina/análisis , Piridoxina/síntesis química , Bases de Schiff/análisis , Programas Informáticos , Espectrofotometría UltravioletaRESUMEN
As a first step in the development of a nucleotide delivery system making use of oligopeptide permease, we have synthesized pyridoxine-peptide-nucleotide conjugates. The nucleotides are bonded on serine residues. The peptides terminate with a pyroglutamate residue. In the first example, the pyridoxine moiety is connected at the end of the peptides, while, in the second example, the pyridoxine moiety is bonded at an aspartic acid residue in a middle position of the peptide. Nucleotides are introduced as phosphoramidites. The synthetic strategy involves a series of protection, deprotection, and coupling reactions, and integrates peptide, nucleotide, and pyridoxine chemistry. The final deprotection step was carried out in basic conditions using 10% K2CO3 in MeOH.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Nucleótidos/síntesis química , Péptidos/síntesis química , Piridoxina/síntesis química , Química Farmacéutica/métodos , Nucleótidos/administración & dosificación , Péptidos/administración & dosificación , Piridoxina/administración & dosificaciónRESUMEN
Gene therapy has emerged as a promising strategy for treatment of various diseases. However, widespread implementation is hampered by difficulties in assessing the success of transfection, in particular, the spatial extent of expression in the target tissue and the longevity of expression. Thus, the development of non-invasive reporter techniques based on appropriate molecules and imaging modalities may help to assay gene expression. We now report the design, synthesis and evaluation of a novel in vivo gene transfection reporter molecule 3-O-(beta-D-galactopyranosyl)-6-fluoropyridoxol (GFPOL) using fluorinated vitamin B(6) as the (19)F NMR sensitive aglycone. GFPOL exhibits the following strengths as an in vivo (19)F NMR gene expression reporter: (a) large chemical shift response to enzyme cleavage (Deltadelta=8.00 ppm); (b) minimal toxicity for substrate or aglycone; (c) good water solubility; (d) good blood stability; (e) pH responsiveness of aglycone.
Asunto(s)
Galactósidos/química , Genes Reporteros , Piridoxina/análogos & derivados , Transfección/métodos , beta-Galactosidasa/análisis , Flúor/química , Galactósidos/síntesis química , Galactósidos/metabolismo , Expresión Génica , Isótopos , Espectroscopía de Resonancia Magnética , Piridoxina/síntesis química , Piridoxina/química , Piridoxina/metabolismo , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismoRESUMEN
The B(6) vitamers have been shown to display beneficial therapeutic effects in cardiovascular related disorders. The design of novel antiplatelet agents using pyridoxine as a template has led to the discovery of a class of novel cardio- and cerebro-protective agents. The present study describes the synthesis of several of these derivatives along with the antiplatelet and antiischemic activity of derivative 16.
Asunto(s)
Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Piridoxina/análogos & derivados , Piridoxina/farmacología , Animales , Isquemia Encefálica/complicaciones , Isquemia Encefálica/patología , Isquemia Encefálica/prevención & control , Modelos Animales de Enfermedad , Humanos , Técnicas In Vitro , Trombosis Intracraneal/etiología , Trombosis Intracraneal/patología , Trombosis Intracraneal/prevención & control , Masculino , Infarto del Miocardio/etiología , Infarto del Miocardio/patología , Infarto del Miocardio/prevención & control , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Piridoxina/síntesis química , Piridoxina/química , Ratas , Ratas Wistar , PorcinosRESUMEN
The synthesis of retinoid vitamin A-vitamin B(6) conjugate analogues from a vitamin B(6) coenzyme analogue and putative HIV-1 trans-activating transcriptional regulatory protein Tat antagonist (Z)-5(')-O-phosphono-pyridoxylidenerhodanine (B6PR) monosodium salt hemiheptadecahydrate [(Z)-B6PRNa8.5H(2)O] is discussed here. All-trans-retinoic acid (ATRA) is coupled to B6PR by a modified Stork enamine acylation. It results in a product library of more than eight compounds, each with at least one intact all-trans or 13-cis vitamin A double bond system. This yellow oily concentrate mixture was subjected to matrix-assisted laser desorption/ionization-time-of-flight (MALDI-ToF) mass spectrometry (MS), UV/VIS-spectrophotometry, and proton nuclear magnetic resonance spectroscopy (1H-NMR). The chemical structures of six components of the concentrate mixture could be established by combination of these analytical methods. The two main components are 65% 2(')C,3O-(all-trans-retinylidyne)B6PT (B6RA) and 25% 2(')C-(all-trans-retinoyl)B6PT, chemically derived from (5RS)-5-(5(')-O-phosphono-pyridoxyl)-2,4-thiazolidinedione (B6PT). This new retinoid selection could be of further interest in antiviral applications, especially treating conditions caused by RNA viruses like HIV.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Productos del Gen tat/antagonistas & inhibidores , Piridoxina/síntesis química , Retinoides/química , Rodanina/síntesis química , Vitamina A/química , Vitamina B 6/química , Secuencia de Aminoácidos , Fármacos Anti-VIH/química , Productos del Gen tat/química , Sustancias Macromoleculares , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Estructura Molecular , Piridoxina/análogos & derivados , Rodanina/análogos & derivados , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrofotometría , Espectrofotometría Ultravioleta , Relación Estructura-Actividad , Tretinoina/químicaRESUMEN
Heating a dilute solution of NH3 and glycoaldehyde gives a large family of pyridines substituted with the same functional groups as occur in the forms of vitamin B6. Thus, vitamin B6-like molecules could have been present on the early Earth and could have been available for catalysis of primitive transamination reactions. Ethanolamine and N-methylethanolamine are also formed as major products. These are choline-like molecules, the latter of which is apparently formed by a prebiotic methylation process.
Asunto(s)
Piridoxina/síntesis química , Amoníaco , Calor , Metilación , Piridoxina/análogos & derivados , Piridoxina/químicaRESUMEN
We have synthesized a series of novel fluorinated vitamin B6 analogues (6-fluoropyridoxol derivatives) as potential 19F NMR pH indicators for use in vivo. Modifications included addition of aldehyde, carboxyl or aminomethyl groups at the 4- or 5-ring position, and examination of a trifluoromethyl moiety as an internal chemical shift standard. The variation in chemical shift with respect to acid-base titration showed pKa values in the range 7.05-9.5 with a chemical shift sensitivity in the range 7.4-12 ppm. Several of the molecules readily cross cell membranes providing estimates of both intra- and extra-cellular pH in whole blood. 6-Fluoropyridoxamine (6-FPAM) exhibits a pKa = 7.05, which is closer to normal physiological pH than the parent molecule 6-fluoropyridoxol (6-FPOL) (pKa = 8.2), and should thus, be useful for precise and accurate measurements of pH in vivo. Enhanced spectral resolution for 6-FPAM over 6-FPOL is demonstrated in whole blood and the perfused rat heart.