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A new series of heteroaryl nitrones were synthesized and evaluated as free radical traps due to the results showed in our previous report. The physicochemical characterization of these new nitrones by electron spin resonance (ESR) demonstrated their high capability to trap and stabilize different atom centered free radicals generated by the Fenton reaction. Additionally, we intensely studied them in terms of their physicochemical properties. Kinetic studies, including the use of a method based on competition and the hydroxyl adduct decay, gave the corresponding rate constants and half-lives at the physiological pH of these newly synthesized nitrones. New nitrones derived from quinoxaline 1,4-dioxide heterocycles were more suitable than DMPO to trap hydroxyl free radicals with a half-life longer than two hours. We explain some of the results using computational chemistry through density functional theory (DFT).

Eight new platinum(II) complexes with 3-(5-nitrofuryl)acroleine thiosemicarbazones showing anti-trypanosomal activity were synthesized, characterized and in vitro evaluated. Most of the complexes showed IC(50) values in the micromolar range against two different strains of Trypanosoma cruzi, causative agent of Chagas disease (American Trypanosomiasis). In addition, most of the newly developed complexes, together with the analogous platinum 5-nitrofuraldehyde containing thiosemicarbazones previously reported, resulted more active than the reference trypanocidal drug nifurtimox on the infective trypomastigote form of the parasite. Their capacity to produce free radicals that could lead to parasite death was evaluated by ESR experiments in the parasite and by respiration measurements. Compounds were tested for their DNA interaction ability. Results showed that some of the compounds could act as dual inhibitors in the parasite, through production of toxic free radicals and interaction with DNA. All the results were compared with those previously reported for the free ligands, the analogous palladium(II) compounds and the previously reported series of platinum(II) compounds.

Cyclic voltammetry (CV) and electron spin resonance (ESR) techniques were used in the investigation of novel palladium complexes with bioactive thiosemicarbazones derived from 5-nitrofurane or 5-nitrofurylacroleine. Sixteen palladium complexes grouped in two series of the formula [PdCl(2)HL] or [PdL(2)] were studied. ESR spectra of the free radicals obtained by electrolytic reduction were characterized and analyzed. The ESR spectra showed two different hyperfine patterns. The stoichiometry of the complexes does not seem to affect significantly the hyperfine constants however we observed great differences between 5-nitrofurane and 5-nitrofurylacroleine derivatives. The scavenger properties of this family of compounds were lower than Trolox.

In the search for new therapeutic tools against Chagas' disease (American Trypanosomiasis) two series of new platinum(II) complexes with bioactive 5-nitrofuryl containing thiosemicarbazones as ligands were synthesized, characterized and in vitro evaluated. Most of the complexes showed IC50 values in the muM range against two different strains of Trypanosoma cruzi, causative agent of the disease, being as active as the anti-trypanosomal drug Nifurtimox. In particular, the coordination of L3 (4-ethyl-1-(5-nitrofurfurylidene)thiosemicarbazide) to Pt(II) forming [Pt(L3)2] lead to almost a five-fold activity increase in respect to the free ligand. Trying to get an insight into the trypanocidal mechanism of action of these compounds, DNA and redox metabolism (intra-parasite free radical production) were evaluated as potential parasite targets. Results suggest that the complexes could inhibit parasite growth through a dual mechanism of action involving production of toxic free radicals by bioreduction and DNA interaction.

This study was undertaken to investigate the free radical-scavenging and antioxidant activities of various structurally related hydroquinones including hydroxynaphthalenones and dihydroxyanthracenones. Electron spin resonance spectroscopy and spin trapping techniques were used to evaluate the ability of hydroquinones to scavenge hydroxyl, diphenylpicrylhydrazyl, and galvinoxyl radicals. In addition, the oxygen radical absorbing capacity assay using fluorescein (ORAC-FL) was used to obtain the relative antioxidant capacity of these radicals. The rate constants of the first H atom abstraction by 2,2-diphenyl-2-picrylhydrazyl ( k 2 ), were obtained under pseudo-first-order conditions. The free radical-scavenging activities and k 2 values discriminate well between hydroxynaphthalenones and dihydroxyanthracenones, showing that the latter have better antioxidant properties. The aforementioned experimental data agree with quantum-chemical results demonstrating the relevance of intramolecular H bonding to radical-scavenging activities.

Successful trials with 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ) for Alzheimer's disease treatment prompted renewed interest in assessing whether its therapeutic action is related to the coordination of neurotoxic trace metals, such as Cu(II) and Zn(II). We now report conditional stability constants (K(C')) for CQ Cu(II) and Zn(II) complexes measured in a biological buffer containing Ca(II) and Mg(II) ions. UV-vis spectroscopy and polarography evidenced a 1:2 stoichiometry of Cu(II) and Zn(II) CQ complexes; the K(C')s calculated were: Cu(CQ)(2) 1.2x10(10), and Zn(CQ)(2) 7.0x10(8)M(-2); the CQ affinity for Cu(II) is at least an order of magnitude higher than for Zn(II). To test the possible functional relevance of the Cu(II) CQ complexes in the brain, we bioassayed free Cu(II) concentration by the metal-induced inhibition of ATP-gated currents of the P2X(4) receptor, a predominant brain P2X receptor. CQ reduced concentration-dependently the Cu(II) inhibition of the ATP-gated currents. In view that the stability constant of CQ for Zn(II) is similar to that of Abeta-amyloid for Zn(II), and the fact that CQ may form complexes with Cu(II), even in the presence of competing ions, the present results highlight that the formation of Cu(II) CQ complexes in the brain may act by diminishing free Cu(II) concentrations modifying thereby brain excitability, or favoring the degradation of beta-amyloid plaques or huntingtin, rather than through a specific effect of CQ itself.

The free radical polymerization of vinyl monomers is efficiently inhibited by β-nitrostyrene derivatives. The high reactivity of the growing radicals towards the β-nitro compounds is controlled by the electron-donor character of the macroradical and the electron deficiency of the double bond of the β-nitro derivative. Electron withdrawing substituents at the 4-position of β-nitrostyrene increase markedly the inhibition rate. The inhibition efficiency of β-nitrostyrene towards electron deficient monomer double bonds is strongly reduced. Polymerization rates and 1 H NMR results show that the β-nitrostyrene derivatives act as strong inhibitors of the polymerization through a mechanism that involves the release of NO 2 .

The polymerization rate of methyl methacrylate photoinitiated by p-nitroacetanilide in the presence of triethylamine was measured as a function of the amine concentration in different media. The polymerization is more efficient in nonpolar medium (benzene/monomer). ESR studies show the formation of a nitro and an amino free radical, which are formed by photoinduced proton transfer from the amine to the nitro group. The amine radical is the active species that adds to the monomer.

The photolysis of trans-β-nitro-βmethylstyrene in acetonitrile solution gives the cisisomer with a quantum yield of 0.8. Addition of triethylamine to the system leads to a small decrease in the photoisomerization quantum yield and the appearance of a strong EPR signal. This signal remains for several hours at the end of the irradiation. It is demonstrated that the EPR signal is associated to an intermediary produced during the triethylamine catalyzed thermal back formation of the trans isomer. This intermediary bears an unpaired electron mostly associated to the nitro group and suggest that the thermal back reaction takes place by an initial electron transfer from the amine to the nitro group, leading to a long lived zwitterionic biradical.

In the chromophore-quencher complex fac-[Re(Aqphen)(CO)(3)(py-PTZ)](+) (Aqphen is 12,17-dihydronaphtho[2,3-h]dipyrido[3,2-a:2',3'-c]-phenazine-12,17-dione; py-PTZ is 10-(4-picolyl)phenothiazine), Aqphen is a dppz derivative, containing a pendant quinone acceptor at the terminus of a rigid ligand framework. This introduces a third, low-lying, ligand-based pi acceptor level localized largely on the quinone fragment. Laser flash excitation of fac-[Re(Aqphen)(CO)(3)(py-PTZ)](+) (354.7 nm; in 1,2-dichloroethane) results in the appearance of a relatively long-lived transient that decays with tau(298K) = 300 ns (k = 3.3 x 10(6) s(-)(1)). Application of transient absorption, time-resolved resonance Raman, and time-resolved infrared spectroscopies proves that this transient is the redox-separated state fac-[Re(I)(Aqphen(*)(-)())(CO)(3)(py-PTZ(*)(+)())](+) in which the excited electron is localized largely on the quinone portion of the Aqphen ligand.

Cyclic voltamograms of the solvatochromic dye 5-nitro-5′-dimethylamino-2,2′-bisthiophene (1), introduced recently as a sensitive π* probe, were recorded in different solvents. An EPR spectrum of the anionic radical of 1 in DMSO was obtained and compared with other spectra of analogous substituted bisthiophene radicals. It was found that the presence of a donor– acceptor pair of substituents in 1−⋅ reduces significantly the rotational barrier of the radical compared with the unsubstituted bithienyl radical anion 2−⋅. This is the result of an electronic repulsion between the donor ring fragment and the added electron in the coplanar radical, which does not exist in 2−⋅. © 1998 John Wiley & Sons, Ltd.

The polymerization rate of methyl methacrylate photosensitized by p-nitroacetanilide in the presence of triethylamine was measured as a function of the amine and monomer concentrations. The polymerization proceeds readily in high-polarity media (acetonitrile/monomer) but is negligible in nonpolar media. The polymerization rate increases with the amine concentration up to 0.15M. Further increase in amine concentration does not change the polymerization rate. A similar behavior was observed for the photobleaching of the nitro compound. ESR studies show the formation of a nitro and an amine free radical, the latter free radical being the active species that adds to the monomer. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 3095–3100, 1997

The formation of paramagnetic species from oncocalyxone A in aprotic medium was confirmed by performing in situ electrochemical-electron spin resonance (E-ESR) experiments. The high delocalization of the radical generated at the first reduction potential is clearly evidenced by the hyperfine coupling of H-9 with the larger coupling constant, besides the couplings at the H-3 (close to quinone) and H-7 (far from the quinone nucleus) positions. In protic medium, together with pH dependence experiments, oncocalyxone A showed to be DNA-reactive through experiments with DNA sensors. Its reaction with N-acetylcysteine, with structural characterization of the addition products, proved its ability as Michael acceptor. Both aspects are important in terms of biological/pharmacological activities and indicate the present models as important tools in the screening of biologically active compounds. A formação de espécies paramagnéticas a partir da oncocalixona A em meio aprótico foi confirmada pela realização de experimentos eletroquímicos in situ em conjunto com ressonância de spin eletrônico (E-ESR). A alta deslocalização do radical gerado no primeiro potencial de redução está claramente evidenciada pelo acoplamento hiperfino do H-9 com a maior constante de acoplamento, além dos acoplamentos nas posições H-3 (próximo à quinona) e H-7 (distante do núcleo quinônico). Em meio prótico, além dos experimentos de dependência com o pH, oncocalixona A mostrou-se DNA-reativa por meio de experimentos eletroquímicos com sensores de DNA. Sua reação com N-acetilcisteína, com caracterização estrutural dos produtos de adição, evidencia sua habilidade como aceptor de Michael. Ambos os aspectos são importantes em termos de atividades biológicas/farmacológicas e indicam os presentes modelos como ferramentas importantes na avaliação de compostos biologicamente ativos.

A new series of heteroaryl nitrones, 1-7, bearing furoxanyl and thiadiazolyl moieties, were evaluated for their free radical-trapping properties. The physicochemical characterization by electron paramagnetic resonance (EPR) demonstrated its capability to trap and stabilize oxygen-, carbon-, sulfur-, and nitrogen-centered free radicals. The 4-furoxanyl nitrone 3 (FxBN), alpha(Z)-(3-methylfuroxan-4-yl)-N-tert-butylnitrone, showed appropriate solubility in aqueous solution and taking into account that this physicochemical property is very important for biological applications, we studied it deeply in terms of its trapping and kinetic behaviors. For this, kinetic studies of the hydroxyl adduct decay gave rate constants k(ST) of 1.22x10(10)dm(3)mol(-1)s(-1) and half-live up to 7200s at physiological pH, without any artifactual signals. The ability of FxBN to directly traps and stabilizes superoxide free radical, with a half-life of 1620s at physiological pH, was also demonstrated. Besides, FxBN-hydroxyl and -superoxide adducts exhibited distinct and characteristic EPR spectral patterns. Finally, we confirmed the ability of FxBN to act as spin trap in a specific biological system, that is, in the free radical production of experimental anti-trypanosomatid drugs using Trypanosoma cruzi microsomes as biological system. Moreover, previous observations of low FxBN toxicity transform it in a good candidate for in vivo spin trapping.

The reduction properties of four acceptor polipyridyl ligands modified with quinones were studied by different experimental methods, as cyclic voltammetry and ESR spectroscopy, and by theoretical calculations. ESR spectra for the reduced ligands show different patterns among them, suggesting that the quinone moiety plays an important role in the delocalization of the received electron. The hyperfine coupling constants calculated for the magnetic nucleus were in good agreement with experimental data. The results were additionally interpreted with the help of two theoretical predictors: the electrophilicity index and the Fukui function obtained through the spin density. The results suggest that 12,17-dihydronaphtho-[2,3-h]dipyrido[3,2-a:2′,3′-c]-phenazine-12,17-dione, Aqphen, shows the most promising behavior to be employed as an acceptor ligand in complexes with potential application in NLO devices.

The electron spin resonance (ESR) spectra of free radicals obtained by electrolytic reduction of triazolopyridyl pyridyl ketones and dipyridyl ketones derivatives were measured in dimethylsulfoxide (DMSO). The hyperfine patterns indicate that the spin density delocalization is dependent of the rings presented in the molecule. The electrochemistry of these compounds was characterized using cyclic voltammetry, in DMSO as solvent. When one carbonyl is present in the molecule one step in the reduction mechanism was observed while two carbonyl are present two steps were detected. The first wave was assigned to the generation of the correspondent free radical species, and the second wave was assigned to the dianion derivatives. The phase–solubility measurements indicated an interaction between molecules selected and cyclodextrins in water. These inclusion complexes are 1:1 with βCD, and HP-βCD. The values of Ks showed a different kind of complexes depending on which rings are included. AM1 and DFT calculations were performed to obtain the optimized geometries, theoretical hyperfine constants, and spin distributions, respectively. The theoretical results are in complete agreement with the experimental ones.

A series of tricarbonyl rhenium(I) complexes of the type fac-[ReI(CO)3(ppl)(L)]0/+, where ppl is pyrazino[2,3-f][1,10]phenanthroline, and where L is Cl−, TfO−, 4-(tert-butyl)pyridine (tBu-py), 4-methoxypyridine (MeO-py), 4,4′-bipyridyl (bpy), or 10-(picolin-4-yl)phenothiazine (pptz), were synthesized and fully characterized. In all complexes, an increment in the electron-acceptor properties of ppl compared to the free ligand was observed. This effect was more significant for pyridine-type ligands, especially for pptz, compared to Cl− or TfO−. The properties of fac-[Re(CO)3(ppl)(pptz)]PF6 were compared with those of the analogous compound fac-[Re(CO)3(dppz)(pptz)]PF6, where dppz is dipyrido(3,2-a : 2′,3′-c)phenazine, the goal being to generate long-lived excited charge-transfer (CT) states. In this respect, fac-[Re(CO)3(ppl)(pptz)]PF6 seems to be a promising candidate.

The ESR spectra of radicals obtained by electrolytic reduction of 2-acylpyridines and 6,6′-diacyl-2,2′-bipyridines were measured in dimethylsulfoxide (DMSO) and analyzed by quantum chemical calculations. The electrochemistry of these compounds was characterized using cyclic voltammetry, in DMSO solvent. The results showed a two step reduction mechanism, first wave was assigned to the generation of the correspondent free radical species, and the second wave was assigned to the dianion derivatives. AM1 and DFT calculations were performed to obtain the optimized geometries, theoretical hyperfine constants, and spin distributions, respectively. The theoretical results are in complete agreement with the experimental ones.

The reduction of several nitrobenzenes bearing electron-donor and electron-withdrawing substituents in the 4-position by triethylamine in acetonitrile was studied by cyclic voltammetry, EPR spectroscopy, and steady-state photolysis. The electrochemical reduction of nitro compounds showed a reversible cathodic wave corresponding to one electron transfer, and forms the nitrobenzene radical anion. The reduction potentials were well correlated with the hyperfine nitrogen coupling constants of the radical anion and with the donor-acceptor characteristics of the 4-substituent. The photoreduction of nitro compounds in the presence of triethylamine gave the nitrobenzene radical anion. EPR spin trapping experiments showed that the α-aminoethyl radical is formed only in the photolysis of nitrobenzenes with electron-donating substituents. These compounds in the presence of the amine were efficient photoinitiators of the methyl methacrylate polymerization. The polymerization rate increases with the amine concentration reaching a constant value. Similar behaviour was observed for the photobleaching quantum yield. These results indicate that the photobleaching and the reaction that leads to radicals able to add to the monomer come from the interaction of the triplet state of the nitro compound with the amine followed by proton transfer within the geminate ion pair giving the neutral radicals. In the absence of monomer, nitrosobenzene appeared to be the primary product. The polymerization in the presence of electron-withdrawing substituted nitrobenzenes was negligible. This is in agreement with the lack of α-aminoalkyl radical formation.