RESUMO
There has been an increasing interest in the study of fluorinated derivatives of gamma-aminobutyric acid (GABA), an acetylcholine (AC) analog. This work reports a theoretical study on the effect of an α-carbonyl fluorination in AC, aiming at understanding the role of a distant fluorine relative to the positively charged nitrogen on the conformational folding of the resulting fluorinated AC. In addition, the chemical and structural changes were evaluated on the basis of ligand-enzyme (acetylcholinesterase) interactions. In an enzyme-free environment, the fluorination yields conformational changes relative to AC due to the appearance of some attractive interactions with fluorine and a weaker steric repulsion between the fluorine substituent and the carboxyl group, rather than to a possible electrostatic interaction Fâ â â N+ . Moreover, the gauche orientation in the N-C-C-O fragment of AC owing to the electrostatic gauche effect is reinforced after fluorination. For instance, the conformational equilibrium in AC is described by a competition between gauche and anti conformers (accounting for the N-C-C-O dihedral angle) in DMSO, while the population for a gauche conformer in the fluorinated AC is almost 100 % in both gas phase and DMSO. However, this arrangement is disrupted in the biological environment even in the fluorinated derivative (whose bioconformation-like geometry shows a ligand-protein interaction of -84.1â kcal mol-1 against -79.5â kcal mol-1 for the most stable enzyme-free conformation), which shows an anti N-C-C-O orientation, because the enzyme induced-fit takes place. Nevertheless, the most likely bioconformation for the fluorinated AC does not match the bioactive AC backbone nor the most stable enzyme-free conformation, thus revealing the role of fluorination on the bioconformational control of AC.
Assuntos
Acetilcolina/química , Halogenação , Hidrocarbonetos Fluorados/química , Teoria Quântica , Acetilcolina/metabolismo , Hidrocarbonetos Fluorados/síntese química , Conformação Molecular , Método de Monte CarloRESUMO
Two mononuclear MnIII complexes [Mn(3,5-F2salpn)(H2O)2][B(C6H5)4]·2H2O (1·2H2O) and [Mn(3,5-Cl2salpn)(OAc)(H2O)]·H2O (2·H2O), where H2salpn=1,3-bis(salicylidenamino)propane, have been prepared and characterized. The crystal structure of 1·H2O shows that this complex forms µ-aqua dimers with a short Mnâ¯Mn distance of 4.93Å. Under anaerobic conditions, the two complexes are stable in solution and possess trans-diaxial symmetry with the tetradentate Schiff base ligand symmetrically arranged in the equatorial plane. When left in air, these complexes slowly dimerize to yield high-valent [MnIV2(3,5-X2-salpn)2(µ-O)2] in which each X2-salpn ligand wraps the two Mn ions. This process is favored in basic medium where the deprotonation of the bound water molecule is concomitant with air oxidation. The two complexes catalyze the dismutation of superoxide (superoxide dismutase (SOD) activity) and peroxide (catalase (CAT) activity) in basic medium. The phenyl-ring substituents play an important role on the CAT reaction but have little effect on SOD activity. Kinetics and spectroscopic results indicate that 1 and 2 catalyze H2O2 disproportionation through a cycle involving MnIII2 and MnIV2 dimers, unlike related complexes with a more rigid and smaller chelate ring, which employ MnIII/MnVO monomers.
Assuntos
Antioxidantes , Catalase/química , Complexos de Coordenação , Hidrocarbonetos Clorados , Hidrocarbonetos Fluorados , Manganês/química , Superóxido Dismutase/química , Antioxidantes/síntese química , Antioxidantes/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Hidrocarbonetos Clorados/síntese química , Hidrocarbonetos Clorados/química , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Bases de Schiff/síntese química , Bases de Schiff/químicaRESUMO
Fluorination reactions of medicinal and biologically-active compounds will be discussed. Late stage fluorination strategies of medicinal targets have recently attracted considerable attention on account of the influence that a fluorine atom can impart to targets of medicinal importance, such as modulation of lipophilicity, electronegativity, basicity and bioavailability, the latter as a consequence of membrane permeability. Therefore, the recourse to late-stage fluorine substitution on compounds with already known and relevant biological activity can provide the pharmaceutical industry with new leads with improved medicinal properties. The fluorination strategies will take into account different fluorinating reagents, either of nucleophilic or electrophilic, and of radical nature. Diverse families of organic compounds such as (hetero)aromatic rings, and aliphatic substrates (sp(3), sp(2), and sp carbon atoms) will be studied in late-stage fluorination reaction strategies.
Assuntos
Descoberta de Drogas , Hidrocarbonetos Fluorados/síntese química , Flúor/química , Halogenação , Hidrocarbonetos Fluorados/química , Estrutura MolecularRESUMO
OBJECTIVES: Many natural antioxidants have poor pharmacokinetic properties that impair their therapeutic use. For hydroxycinnamic acids (HCAs) and other phenolic antioxidants, their major drawback is their low lipophilicity and a rapid metabolism. The difluoromethyl group may be considered as a 'lipophilic hydroxyl' due to its hydrogen bond donor and acceptor properties; this prompted us to assess it as a bioisosteric replacement of a phenolic hydroxyl for increasing the lipophilicity of HCAs. METHODS: Six difluoromethyl-substituted methyl cinnamates (4a-c, 5a-c) related to caffeic acid were synthesized and their antioxidant activity evaluated by chemical (FRAP, DPPH scavenging, inhibition of ß-carotene bleaching, at 1-200 µm), electrochemical (differential pulse voltammetry, cyclic voltammetry) and cell-based (inhibition of lipid peroxidation in erythrocytes, at 1 and 50 µm) assays. KEY FNDINGS: Analogues 4a-c and 5a-c were inactive in FRAP and DPPH assays and only those containing a free phenolic hydroxyl (4a and 5a) exhibited electrochemical activity although with high redox potentials. Compounds 4a,b and 5a,b were active in the inhibition of ß-carotene bleaching assay and all analogues inhibited lipid peroxidation in the human erythrocytes assay. CONCLUSIONS: Lipophilic difluoromethyl-substituted cinnamic esters retain radical scavenging capabilities that prove useful to confer antioxidant properties in a non-polar environment.
Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , Ácidos Cumáricos/síntese química , Ácidos Cumáricos/farmacologia , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/farmacologia , Antioxidantes/química , Compostos de Bifenilo/química , Células Cultivadas , Ácidos Cumáricos/química , Eletroquímica , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Ferricianetos/química , Radicais Livres/química , Humanos , Hidrocarbonetos Fluorados/química , Peroxidação de Lipídeos/efeitos dos fármacos , Estrutura Molecular , Oxirredução , Picratos/química , beta Caroteno/químicaRESUMO
This study reports a facile and controllable synthetic method for the preparation of both 1,3- and 1,5-isomers of 4-(3(5)-aryl-3(5)-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamides, as well as a new series of 4-(3-aryl-5-hydroxy-5-(trifluoromethyl)-4,5-dihydropyrazol-1-yl)benzenesulfonamides, from the cyclocondensation reaction of 4-aryl-1,1,1-trifluoro-4-methoxybut-3-en-2-ones or 1-aryl-4,4,4-trifluoro-butane-1,3-diones or their enolic forms with 4-hydrazinylbenzenesulfonamide. All compounds of the new series of 3-substituted 1-(4-benzenesulfonamide)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydropyrazoles were tested for their effect on a pathological pain model in mice. The compounds 3a, 3b, 3c, 3e, and 3f presented anti-hyperalgesic action, while the compounds 3a, 3c, 3d, 3f, and 3g exhibited anti-edematogenic effects, without causing locomotive disorders in animals, thus making them comparable to Celecoxib in an arthritic pain model.
Assuntos
Hidrocarbonetos Fluorados/síntese química , Hiperalgesia/tratamento farmacológico , Sulfonamidas/síntese química , Sulfonamidas/uso terapêutico , Animais , Celecoxib , Modelos Animais de Doenças , Edema/tratamento farmacológico , Edema/patologia , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Hiperalgesia/patologia , Masculino , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Estereoisomerismo , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
Six new fluorinated thiosemicarbazones RC(R')=N-NH-C(S)NH(2) (R = 2,4-C(6)H(3)F(2), R' = H (1); R = 2,5-C(6)H(3)F(2), R' = H (2); R = 2,6-C(6)H(3)F(2), R' = H (3); R = 3,4-C(6)H(3)F(2), R' = H (4); R = 3,5-C(6)H(3)F(2), R' = H (5) and R = 4-C(6)H(4)F, R' = C(6)H(5), (6)) have been prepared. The molecular structures of compounds 1 to 6 have been determined.
Assuntos
Hidrocarbonetos Fluorados/síntese química , Tiossemicarbazonas/síntese química , Benzaldeídos/síntese química , Benzaldeídos/química , Cristalografia por Raios X , Halogenação , Hidrocarbonetos Fluorados/química , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Tiossemicarbazonas/químicaRESUMO
Perfluoroalkyl-substituted compounds are regarded as important components of fluorophors and for the introduction of fluorous tags into organic substrates. Their syntheses in organic solvents are achieved through different methods, among which, the addition of perfluoroalkyl radicals to unsaturated bonds represents a convenient choice. On the other hand, intermolecular radical reactions in water have attracted the attention of synthetic chemists as a strategic route to carbon-carbon bond formation reactions. In this paper we undertook the intermolecular addition of perfluoroalkyl radicals on electron rich alkenes and alkenes with electron withdrawing groups in water, mediated by silyl radicals, and obtained perfluoroalkyl-substituted compounds in fairly good yields. The radical triggering events employed consist of the thermal decomposition of an azo compound and the dioxygen initiation. Our results indicate that for intermolecular carbon-carbon bond formation reactions mediated by (Me(3)Si)(3)SiH, the decomposition of the azo compound 1,1'-azobis(cyclohexanecarbonitrile) (ACCN) is the best radical initiator. We also found that water exerts a relevant solvent effect on the rates of perfluoroalkyl radical additions onto double bonds and the H atom abstraction from the silane. Our account provides a versatile and convenient method to achieve perfluoroalkylation reactions of alkenes in water to render perfluoroalkylated alkanes as key intermediates in the synthesis of fluorophors and other fluorinated materials. This is the first report where perfluoroalkyl-substituted alkanes are synthesized through intermolecular radical carbon-carbon bond formation reactions in water, mediated by silyl radicals.
Assuntos
Alcenos/química , Hidrocarbonetos Fluorados/síntese química , Silicones/química , Água/química , Alquilação , Radicais Livres/química , Hidrocarbonetos Fluorados/química , Estrutura Molecular , EstereoisomerismoRESUMO
This paper reports for the first time the synthesis and characterization of trifluoromethyl fluoroformyl trioxicarbonate, CF(3)OC(O)OOOC(O)F. The new trioxide is obtained from the gas-phase photolytic reaction of CF(3)C(O)OC(O)CF(3) and FC(O)C(O)F at 223-228 K. It is a very thermally labile molecule that decomposes at room temperature by rupture of either of the CF(3)OC(O)O-O-OC(O)F bonds. These bonds are nonequivalent, and a branching ratio of 0.8 for fragmentation through the CF(3)OC(O)OO-OC(O)F bond was obtained. Unambiguous identification was possible through reaction of the trioxide with an excess of NO(2). Potential-energy surfaces (PES) of the different rotamers were studied by the B3LYP/6-311+G* method, and analysis of the IR frequency of the possible mixture of rotamers agrees excellently with the experimental IR spectrum. This molecule is the first nonsymmetric acyl trioxide reported in the literature.
Assuntos
Carbonatos/química , Hidrocarbonetos Fluorados/química , Óxidos/química , Carbonatos/síntese química , Simulação por Computador , Hidrocarbonetos Fluorados/síntese química , Modelos Químicos , Óxidos/síntese química , Espectrofotometria Infravermelho , TemperaturaRESUMO
The geometric structure and conformational properties of S-(fluoroformyl)O-(trifluoroacetyl) thioperoxide, FC(O)S-OC(O)CF3, were investigated by gas electron diffraction, matrix isolation infrared spectroscopy, and quantum chemical calculations (B3LYP with the 6-31G and aug-cc-pVTZ basis sets and MP2 with the 6-31G basis set). The experimental methods result in a mixture of two conformers with gauche conformation around the S-O bond. In the main conformer (82(7)% according to GED at 298 K), the C=O bond of the FC(O) group is oriented syn with respect to the S-O bond and phi(C-S-O-C) = 75(3) degrees . In the minor conformer (18(7)%), this C=O is oriented anti. Both conformers possess syn orientation of the C=O bond of the CF3C(O) group. The conformational properties and geometric parameters are reproduced reasonably well by the quantum chemical calculations, except for the S-O bond length, which is predicted too long by 0.04 A (B3LYP/aug-cc-pVTZ).
Assuntos
Fluoracetatos , Hidrocarbonetos Fluorados/química , Peróxidos/química , Ácido Trifluoracético/química , Elétrons , Gases/química , Hidrocarbonetos Fluorados/síntese química , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Peróxidos/síntese química , Teoria Quântica , Sensibilidade e Especificidade , Espectrofotometria Infravermelho/métodos , Ácido Trifluoracético/síntese químicaRESUMO
A simple and regiospecific synthesis of 4-alkoxy(amino)-2-trifluoromethyl pyrroles from 5-azido-4-alkoxy(amino)-1,1,1-trifluoro-pent-3-en-2-ones by an aza-Wittig cyclization of aminophosphoranes is described. The structures of the pyrroles and their synthetic intermediates were supported by NMR and HRMS analysis.