RESUMEN
The syntheses of four new tunable homogeneous organic reductants based on a tetraaminoethylene scaffold are reported. The new reductants have enhanced air stability compared to current homogeneous reductants for metal-mediated reductive transformations, such as cross-electrophile coupling (XEC), and are solids at room temperature. In particular, the weakest reductant is indefinitely stable in air and has a reduction potential of -0.85 V versus ferrocene, which is significantly milder than conventional reductants used in XEC. All of the new reductants can facilitate C(sp2)-C(sp3) Ni-catalyzed XEC reactions and are compatible with complex substrates that are relevant to medicinal chemistry. The reductants span a range of nearly 0.5 V in reduction potential, which allows for control over the rate of electron transfer events in XEC. Specifically, we report a new strategy for controlled alkyl radical generation in Ni-catalyzed C(sp2)-C(sp3) XEC. The key to our approach is to tune the rate of alkyl radical generation from Katritzky salts, which liberate alkyl radicals upon single electron reduction, by varying the redox potentials of the reductant and Katritzky salt utilized in catalysis. Using our method, we perform XEC reactions between benzylic Katritzky salts and aryl halides. The method tolerates a variety of functional groups, some of which are particularly challenging for most XEC transformations. Overall, we expect that our new reductants will both replace conventional homogeneous reductants in current reductive transformations due to their stability and relatively facile synthesis and lead to the development of novel synthetic methods due to their tunability.
Asunto(s)
Alquenos/química , Aminas/química , Compuestos Heterocíclicos con 1 Anillo/química , Sustancias Reductoras/química , Alquenos/síntesis química , Aminas/síntesis química , Compuestos Heterocíclicos con 1 Anillo/síntesis química , Estructura Molecular , Oxidación-Reducción , Sustancias Reductoras/síntesis químicaRESUMEN
Amine-peroxide redox polymerization (APRP) has been highly prevalent in industrial and medical applications since the 1950s, yet the initiation mechanism of this radical polymerization process is poorly understood so that innovations in the field are largely empirically driven and incremental. Through a combination of computational prediction and experimental analysis, we elucidate the mechanism of this important redox reaction between amines and benzoyl peroxide for the ambient production of initiating radicals. Our calculations show that APRP proceeds through SN2 attack by the amine on the peroxide but that homolysis of the resulting intermediate is the rate-determining step. We demonstrate a correlation between the computationally predicted initiating rate and the experimentally measured polymerization rate with an R2 = 0.80. The new mechanistic understanding was then applied to computationally predict amine reductant initiators with faster initiating kinetics. This led to our discovery of N-(4-methoxyphenyl)pyrrolidine (MPP) as amine reductant, which we confirmed significantly outperforms current state-of-the-art tertiary aromatic amines by â¼20-fold, making it the most efficient amine-peroxide redox initiator to date. The application of amines with superior kinetics such as MPP in APRP could greatly accelerate existing industrial processes, facilitate new industrial manufacturing methods, and improve biocompatibility in biomedical applications conducted with reduced initiator concentrations yet higher overall efficiency.
Asunto(s)
Aminas/química , Peróxidos/química , Sustancias Reductoras/química , Aminas/síntesis química , Estructura Molecular , Oxidación-Reducción , Polimerizacion , Sustancias Reductoras/síntesis químicaRESUMEN
Thiol(-click) chemistry has been extensively investigated to conjugate (bio)molecules to polymers. Handling of cysteine-containing molecules may however be cumbersome, especially in the case of fast-oxidizing coiled-coil-forming peptides. In the present study, we investigated the practicality of a one-pot process to concomitantly reduce and conjugate an oxidized peptide to a polymer. Three thiol-based conjugation chemistries (vinyl sulfone (VS), maleimide, and pyridyldithiol) were assayed along with three reducing agents (tris(2-carboxyethyl)phosphine (TCEP), dithiothreitol, and ß-mercaptoethanol). Seven out of the nine possible combinations significantly enhanced the conjugation yield, provided that an adequate concentration of reductant was used. Among them, the coincubation of an oxidized peptide with TCEP and a VS-modified polymer displayed the highest level of conjugation. Our results also provide insights into two topics that currently lack consensus: TCEP is stable in 10 mM phosphate buffered saline and it reacts with thiol-alkylating agents at submillimolar concentrations, and thus should be carefully used in order to avoid interference with thiol-based conjugation reactions.
Asunto(s)
Química Clic/métodos , Péptidos/química , Polímeros/química , Sustancias Reductoras/química , Compuestos de Sulfhidrilo/química , Alquilación , Maleimidas/síntesis química , Maleimidas/química , Oxidación-Reducción , Péptidos/síntesis química , Polímeros/síntesis química , Sustancias Reductoras/síntesis química , Compuestos de Sulfhidrilo/síntesis química , Sulfonas/síntesis química , Sulfonas/químicaRESUMEN
Eight anthocyanidins, seven anthocyanins and two synthesized 4'-hydroxy flavyliums were examined as hydrogen donors to DPPH, ABTS and hydroxyl radicals, and as electron donors in the FRAP assay. Most compounds gave better activities than trolox and catechol. A structure-activity relationship (SAR) study showed that, in the absence of the 3-OH group, radicals of the 4, 5 or 7-OH groups can only be stabilized by resonance through pyrylium oxygen, while 3-OH group improved hydrogen atom donation because of the stabilization by anthocyanidin semiquinone-like resonance. Electron donation was also enhanced by the 3-OH group. Both anthocyanidins and their respective anthocyanins showed similar trends and close activities. Different types of sugar unit bonded to the 3-OH group or counter ion had minor effect on activities. The catechol structure improved both hydrogen and electron donation. Compounds lacking the catechol structure had a decreasing order of H-atom and electron donation (Mv>Pn>Pg>Ap>4'-OH-flavylium) consistent with the decreasing number of their hydroxyl and/or methoxy groups.
Asunto(s)
Antocianinas/química , Antioxidantes/química , Sustancias Reductoras/química , Antocianinas/síntesis química , Antioxidantes/síntesis química , Sustancias Reductoras/síntesis química , Relación Estructura-ActividadRESUMEN
Palladium/chiral diphosphine-catalyzed umpolung cyclization of allylic acetate-aldehyde using formate as a terminal reductant affords cis-disubstituted pyrrolidine, tetrahydrofuran, and spiro carbocycle in high enantioselectivity. The formate does not cause allylpalladium reduction under the catalysis. The highly stereoselective cyclization would proceed through a cationic η(1)-allylpalladium ligated by diphosphine.
Asunto(s)
Acetatos/química , Aldehídos/química , Compuestos Alílicos/química , Compuestos Organometálicos/química , Paladio/química , Sustancias Reductoras/síntesis química , Catálisis , Ciclización , Furanos/síntesis química , Furanos/química , Estructura Molecular , Fosfinas/química , Pirrolidinas/síntesis química , Pirrolidinas/química , Sustancias Reductoras/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
For fifty years, dithiothreitol (DTT) has been the preferred reagent for the reduction of disulfide bonds in proteins and other biomolecules. Herein we report on the synthesis and characterization of 2,3-bis(mercaptomethyl)pyrazine (BMMP), a readily accessible disulfide-reducing agent with reactivity under biological conditions that is markedly superior to DTT and other known reagents.
Asunto(s)
Biología , Disulfuros/química , Pirazinas/química , Sustancias Reductoras/química , Compuestos de Sulfhidrilo/química , Pirazinas/síntesis química , Sustancias Reductoras/síntesis química , Compuestos de Sulfhidrilo/síntesis químicaRESUMEN
Chalcone derivatives have attracted increasing attention due to their numerous pharmacological activities. Changes in their structures have displayed high degree of diversity that has proven to result in a broad spectrum of biological activities. The present study highlights the synthesis of some halogen substituted chalcones 3(a-i) containing the 5-chlorothiophene moiety, their X-ray crystal structures and the evaluation of possible biological activities such as antibacterial, antifungal and reducing power abilities. The results indicate the tested compounds show a varied range of inhibition values against all the tested microbial strains. Compound 3c with a p-fluoro substituent on the phenyl ring exhibits elevated antimicrobial activity, whereas the compounds 3e and 3f displayed the least antimicrobial activities. The compounds 3d, 3e, 3f and 3i showed good ferric and cupric reducing abilities, and the compounds 3b and 3c showed the weakest reducing power in the series.
Asunto(s)
Antibacterianos/síntesis química , Antifúngicos/síntesis química , Chalconas/síntesis química , Antibacterianos/farmacología , Antifúngicos/farmacología , Antioxidantes/síntesis química , Antioxidantes/farmacología , Chalconas/farmacología , Cristalografía por Rayos X , Fusarium/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Enlace de Hidrógeno , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Sustancias Reductoras/síntesis química , Sustancias Reductoras/farmacología , Tiofenos/síntesis química , Tiofenos/farmacologíaRESUMEN
We report on the synthesis and use of a new supported reagent consisting in tris(2-carboxyethyl)phosphine (TCEP) immobilized on hydrophilic PEG based resin beads. Used in conjunction with a 5 min microwave (MW) irradiation, "supported TCEP" reduced disulfide bridges in free thiols in peptides having two or more cysteine residues. Separation of reaction products from reducing agent was easily performed by simple filtration.
Asunto(s)
Disulfuros/química , Péptidos/química , Fosfinas/química , Sustancias Reductoras/química , Secuencia de Aminoácidos , Microondas , Datos de Secuencia Molecular , Oxidación-Reducción , Fosfinas/síntesis química , Sustancias Reductoras/síntesis químicaRESUMEN
The complex Ru(II)(NH(3))(2)(o-benzoquinonediimine)Cl(2) undergoes a reversible apparent acid/base reaction, although it has no obvious basic lone pairs. The reaction is a proton-assisted disproportionation yielding an oxidant ([Ru(III)(NH(3))(2)(o-benzoquinonediimine)Cl(2)](+)) and a reductant ([Ru(III)(NH(3))(2)(o-phenylenediamine)Cl(2)](+)). These species were characterized by electrochemistry, ultraviolet-visible light (UV-vis), vibrational (infrared (IR) and Raman), mass and electron paramagnetic resonance (EPR) spectroscopy, and X-ray structural analysis. The reaction is shown to be downhill from an isodesmic calculation. Three different isosbestic interconversions of the parent and product species are demonstrated. The electronic structures of these species were analyzed, and their optical spectra assigned, using density functional theory (DFT) and time-dependent DFT. This disproportionation of a noninnocent ligand complex may be relevant to the application of noninnocent ligands in organometallic catalysis and in the biological milieu.
Asunto(s)
Compuestos Organometálicos/química , Compuestos Organometálicos/síntesis química , Oxidantes/síntesis química , Protones , Sustancias Reductoras/síntesis química , Rutenio/química , Cristalografía por Rayos X , Espectroscopía de Resonancia por Spin del Electrón , Ligandos , Modelos Moleculares , Oxidantes/química , Teoría Cuántica , Sustancias Reductoras/químicaRESUMEN
Most evidence indicates that platinum(IV) prodrugs are rapidly reduced under physiological conditions by biologically relevant reducing agents, such as ascorbic acid and glutathione; however, the precise mechanisms of reduction are not fully understood, thus preventing rational design of compounds with better pharmacological properties. In the present study, reduction of three all-trans platinum(IV) compounds of formula [PtCl(2)(CH(3)COO)(2)LL'] (LL' = {E-HNâC(CH(3))OCH(3)}(2), 1c, (H(3)N)(cyclohexylamine), 2c, and (H(3)N)(1-adamantylamine), 3c) by two biologically relevant reductants (ascorbic acid and glutathione) and by a classical coordination chemistry reductant (triphenylphosphine) has been investigated. Reduction by triphenylphosphine and glutathione leads, in all cases examined, to loss of the two chlorides and formation of the diacetato species trans-[Pt(CH(3)COO)(2)LL']. This is in accord with an "inner-sphere" redox process in which a chlorido ligand bridges the reductant with the platinum(IV) center. In contrast, reduction by ascorbic acid/sodium ascorbate 1:1 leads, in addition to the diacetato complex, also to formation of a significant amount of dichlorido species, particularly in the case of 1c (31%) and to a lesser extent of 3c (16%). The latter results indicate that ascorbic acid is less efficient to promote an inner-sphere redox process (attack on a chlorido ligand), therefore allowing participation of an "outer-sphere" mechanism, ultimately leading to formation of the more stable dichlorido species. The dependence of the yield of diacetato species upon the steric hindrance of the carrier ligand (69%, 84%, and 95% for 1c, 3c, and 2c, respectively) points to the possible participation of a second type of inner-sphere mechanism in which the interaction between the ascorbate and a chlorido ligand of the platinum(IV) substrate is mediated by a platinum(II) catalyst, the transition state resembling that of a platinum(II)-catalyzed ligand substitution at a platinum(IV) center. This investigation demonstrates that different species can be obtained by reduction of a platinum(IV) prodrug (depending upon the configuration of the substrate and the nature of the intervening reducing agent) and can explain some lack of correlation between prodrug and putative active species as well as contrasting literature results.
Asunto(s)
Compuestos Organoplatinos/química , Profármacos/química , Sustancias Reductoras/química , Ligandos , Estructura Molecular , Compuestos Organoplatinos/síntesis química , Oxidación-Reducción , Sustancias Reductoras/síntesis química , EstereoisomerismoRESUMEN
Nanoparticles of Al(0) were synthesized by solution reduction process successfully. The influence of parameters on the size of Al(0) nanoparticles were studied and the referential process parameters were obtained. The morphology and structure of the synthesized Al(0) nanoparticles were characterized by Transmission Electron Microscopy (TEM), Powder X-ray Diffraction (XRD), Thermal Gravimetric Analysis (TGA), QELS Data and Infrared Spectroscopy (IR). The results show that nanoparticles of Al(0) are of high purity. XRD analysis revealed all relevant Bragg's reflection for crystal structure of Al metal. XRD spectrum also indicates there is no oxidation of Al(0) nanoparticles to aluminum oxide. TEM showed nearly uniform distribution of the particles in methanol and it was confirmed by QELS. Al(0) nanoparticles can be synthesized easily by reducing agent and are quite stable too.
Asunto(s)
Aluminio/química , Nanopartículas/química , Poliaminas/química , Sustancias Reductoras/química , Concentración de Iones de Hidrógeno , Nanopartículas/ultraestructura , Poliaminas/síntesis química , Sustancias Reductoras/síntesis química , TemperaturaRESUMEN
A novel double-step reduction procedure for the synthesis of gold nanoparticles (AuNPs) using amino acid ionic liquids has been employed. 1-Dodecyl-3-methyl imidazolium tryptophan ([C(12)mim]Trp) and 1-ethyl-3-methyl imidazolium tryptophan ([C(2)mim]Trp) were used for this synthesis. The synthesized AuNPs were characterized by UV-vis spectroscopy, transmission electron microscopy and dynamic light scattering. The behavior of these AuNPs were also probed in a biological media. It was proven that AuNPs synthesized at [C(12)mim]Trp have more stability than AuNPs synthesized at [C(2)mim]Trp due to the longer alkyl chain of the imidazolium moiety. The solubility test shows that the resultant AuNPs have a hydrophilic nature. Finally, it was seen that due to the presence of a biomolecule, namely Trp, in the structure of AuNPs protecting shell, higher stability and biocompatibility was achieved in the biological media.
Asunto(s)
Oro/química , Imidazoles/química , Líquidos Iónicos/química , Nanopartículas del Metal/química , Sustancias Reductoras/química , Triptófano/análogos & derivados , Triptófano/química , Borohidruros/química , Medios de Cultivo/química , Estabilidad de Medicamentos , Imidazoles/síntesis química , Líquidos Iónicos/síntesis química , Nanopartículas del Metal/ultraestructura , Concentración Osmolar , Oxidación-Reducción , Tamaño de la Partícula , Sustancias Reductoras/síntesis química , Solubilidad , Espectrofotometría Ultravioleta , Resonancia por Plasmón de Superficie , Triptófano/síntesis químicaRESUMEN
The reactive oxygen species (ROS) superoxide has been recognized as a critical signal triggering retinal ganglion cell (RGC) death after axonal injury. Although the downstream targets of superoxide are unknown, chemical reduction of oxidized sulfhydryls has been shown to be neuroprotective for injured RGCs. On the basis of this, we developed novel phosphine-borane complex compounds that are cell permeable and highly stable. Here, we report that our lead compound, bis (3-propionic acid methyl ester) phenylphosphine borane complex 1 (PB1) promotes RGC survival in rat models of optic nerve axotomy and in experimental glaucoma. PB1-mediated RGC neuroprotection did not correlate with inhibition of stress-activated protein kinase signaling, including apoptosis stimulating kinase 1 (ASK1), c-jun NH2-terminal kinase (JNK) or p38. Instead, PB1 led to a striking increase in retinal BDNF levels and downstream activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway. Pharmacological inhibition of ERK1/2 entirely blocked RGC neuroprotection induced by PB1. We conclude that PB1 protects damaged RGCs through activation of pro-survival signals. These data support a potential cross-talk between redox homeostasis and neurotrophin-related pathways leading to RGC survival after axonal injury.
Asunto(s)
Axones/fisiología , Boranos/farmacología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos/fisiología , Fármacos Neuroprotectores/farmacología , Fosfinas/farmacología , Células Ganglionares de la Retina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Axones/ultraestructura , Axotomía , Western Blotting , Boranos/farmacocinética , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Muerte Celular , Permeabilidad de la Membrana Celular , Hipertensión Ocular/patología , Traumatismos del Nervio Óptico/tratamiento farmacológico , Traumatismos del Nervio Óptico/patología , Fosfinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Sustancias Reductoras/síntesis química , Sustancias Reductoras/farmacología , Superóxidos/químicaRESUMEN
Coffee, a highly processed food, and Maillard mixtures are able to activate nuclear factor kappaB translocation in macrophages via generation of hydrogen peroxide. In this study, a substructure library was prepared and used to identify Maillard products that are responsible for this effect. Three different Maillard reaction products with aminoreductone substructure (C(6)-aminoreductone, C(4)-aminoreductone, and aminohexose reductone) strongly induce nuclear factor kappaB translocation in macrophages. The effect was almost completely blocked by co-incubation with catalase, indicating that cellular activation was mediated by the ability of the test compounds to generate hydrogen peroxide. The cellular effect of a Maillard mixture, which was produced under conditions favoring aminoreductone formation, could be almost completely related to the presence of C(6)-aminoreductone.
Asunto(s)
Núcleo Celular/efectos de los fármacos , Macrófagos/efectos de los fármacos , Reacción de Maillard , FN-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Sustancias Reductoras/farmacología , Animales , Catalasa/metabolismo , Línea Celular , Núcleo Celular/metabolismo , Cromatografía Líquida de Alta Presión , Manipulación de Alimentos , Peróxido de Hidrógeno/metabolismo , Cetosas/análisis , Cetosas/química , Cetosas/farmacología , Macrófagos/metabolismo , Espectroscopía de Resonancia Magnética , Transporte de Proteínas/efectos de los fármacos , Ratas , Sustancias Reductoras/síntesis química , Sustancias Reductoras/química , Bibliotecas de Moléculas Pequeñas , Espectrofotometría Ultravioleta , Factor de Transcripción ReIA/metabolismoRESUMEN
Schiff base tetraazamacrocyclic ligand, L (C(40)H(28)N(4)) and its complexes of types, [MLX(2)] and [CuL]X(2) (M=Co(II), Ni(II), Zn(II); X=Cl(-), NO(3)(-)) were synthesized and characterized by elemental analyses, mass, (1)H NMR, IR, UV-vis, magnetic susceptibility and molar conductance data. An octahedral geometry has been proposed for all the complexes except the copper(II) complexes which have a square planar environment. The reducing power of the Co(II) and Cu(II) complexes have been checked and compared. The ligand (L) and its complexes have also been screened against different fungi and bacteria in vitro.