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1.
Org Biomol Chem ; 18(27): 5228-5233, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32602492

RESUMO

Three molecular threads incorporating two viologen units attached by an oligo-ethylene glycol chain of variable length and an electron rich naphthalene moiety were prepared. The internal viologen unit is connected to the naphthalene by a rigid linker that prevents the simultaneous complexation of these systems. The axle with the shortest chain (14+) in the presence of CB[8] placed the chain inside the macrocycle in aqueous media. In contrast, the longer chains in 24+ and 34+ allow locating the terminal viologen and the electron rich unit inside the cavity. Upon reduction of the bipyridinium salts, the system behaves like a zip tie relaxing the chain as a consequence of the insertion of both radical cation moieties within the CB[8] and making these switches as potential components for molecular machinery.

2.
Oxid Med Cell Longev ; 2019: 6528106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396304

RESUMO

In the cold environments of the interstellar medium, a variety of molecules in which a hydrogen (H) atom has been replaced by its heavier isotope deuterium (D) can be found. From its emergence, life had to counteract the toxic action of many agents, which posed a constant threat to its development and propagation. Oxygen-reactive species are archaic toxicants that lead to protein damage and genomic instability. Most of the oxidative lesions involve cleavage of C-H bonds and H abstraction. According to free radical chemistry principles, the substitution of D for H in oxidation-sensitive positions of cellular components should confer protection against the oxidative attack without compromising the chemical identity of the compounds. Here, we show that deuterated nucleosides and proteins protect from oxidative damage. Our data suggest a new, subtle but likely role of D in terrestrial life's evolution in that its inclusion in critical biomolecules might have facilitated their resistance during the infinite generations of life entities, cells, and organisms.


Assuntos
Deutério/química , Estresse Oxidativo , Sobrevivência Celular/efeitos dos fármacos , Sistema Livre de Células , Dano ao DNA/efeitos dos fármacos , Radicais Livres/química , Produtos Finais de Glicação Avançada/análise , Humanos , Células Jurkat , Nucleosídeos/química , Nucleosídeos/metabolismo , Nucleosídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica , Proteínas/química , Proteínas/metabolismo
3.
Sci Rep ; 9(1): 11636, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406187

RESUMO

A large number of basic researches and observational studies suggested the cancer preventive activity of vitamin E, but large-scale human intervention trials have yielded disappointing results and actually showed a higher incidence of prostate cancer although the mechanisms underlying the increased risk remain largely unknown. Here we show through in vitro and in vivo studies that vitamin E produces a marked inductive effect on carcinogen-bioactivating enzymes and a pro-oxidant status promoting both DNA damage and cell transformation frequency. First, we found that vitamin E in the human prostate epithelial RWPE-1 cell line has the remarkable ability to upregulate the expression of various phase-I activating cytochrome P450 (CYP) enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), giving rise to supraphysiological levels of reactive oxygen species. Furthermore, our rat model confirmed that vitamin E in the prostate has a powerful booster effect on CYP enzymes associated with the generation of oxidative stress, thereby favoring lipid-derived electrophile spread that covalently modifies proteins. We show that vitamin E not only causes DNA damage but also promotes cell transformation frequency induced by the PAH-prototype benzo[a]pyrene. Our findings might explain why dietary supplementation with vitamin E increases the prostate cancer risk among healthy men.

4.
J Org Chem ; 84(14): 9364-9368, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31203619

RESUMO

The back and forth motions of a crown-ether based wheel along the axis of a bistable rotaxane are triggered by the decarboxylation of 2-cyano-2-phenylpropanoic acid and detected by the oscillation of the EPR nitrogen splitting of a dialkyl nitroxide function mounted within the macrocyclic ring. When the p-Cl derivative of the acid is used, back and forth motions are accelerated. Conversely, with p-CH3 and p-OCH3 derivatives, the back motion is strongly inhibited by the insurgence of collateral radical reactions.

5.
Phys Chem Chem Phys ; 21(7): 3558-3563, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30229755

RESUMO

The synthesis of novel dibenzo-24-crown ether substituted nitroxides and their use as spin probes for the detection of cation guests by EPR are reported. Formation of a host-guest complex between the proposed spin probes and several cations, both organic and inorganic, was evidenced by a significant change in the value of the benzylic and nitrogen EPR hyperfine splittings upon complexation. This favorable feature provided a reliable EPR sensor that is able to selectively distinguish different cationic guests.

6.
Nanoscale ; 10(21): 9908-9916, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29790558

RESUMO

Hybrid systems have great potential for a wide range of applications in chemistry, physics and materials science. Conjugation of a biosystem to a molecular material can tune the properties of the components or give rise to new properties. As a workhorse, here we take a C60@lysozyme hybrid. We show that lysozyme recognizes and disperses fullerene in water. AFM, cryo-TEM and high resolution X-ray powder diffraction show that the C60 dispersion is monomolecular. The adduct is biocompatible, stable in physiological and technologically-relevant environments, and easy to store. Hybridization with lysozyme preserves the electrochemical properties of C60. EPR spin-trapping experiments show that the C60@lysozyme hybrid produces ROS following both type I and type II mechanisms. Due to the shielding effect of proteins, the adduct generates significant amounts of 1O2 also in aqueous solution. In the case of type I mechanism, the protein residues provide electrons and the hybrid does not require addition of external electron donors. The preparation process and the properties of C60@lysozyme are general and can be expected to be similar to other C60@protein systems. It is envisaged that the properties of the C60@protein hybrids will pave the way for a host of applications in nanomedicine, nanotechnology, and photocatalysis.


Assuntos
Fulerenos/química , Muramidase/química , Água/química , Detecção de Spin
7.
Chemistry ; 24(47): 12370-12382, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-29660175

RESUMO

Operating molecular machines are based on switchable systems whose components can be set in motion in a controllable fashion. The presence of nonsymmetrical elements is a mandatory requirement to obtain and demonstrate the unidirectionality of motion. Calixarene-based macrocycles have proved to be very efficient hosts in the design of oriented rotaxanes and of pseudorotaxanes with strict control over the direction of complexation. A series of two-station rotaxanes based on bipyridinium-ammonium axles was synthesized and characterized. A recently reported supramolecularly assisted strategy for the synthesis of different orientational isomers was exploited, and the ammonium unit was identified as a proper secondary station for the calixarene. Displacement of the macrocycle was triggered by electrochemical reduction of the bipyridinium primary station, and it was shown that the shuttling is influenced both by the length of the chain of the axle component and by the position of the secondary station with respect to the calixarene rims.

8.
Phys Chem Chem Phys ; 20(12): 8071-8076, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29516066

RESUMO

A mechanism based on the sequential absorption of two photons by the components of a redox couple has been recently proposed for catalysis of the energetically demanding reduction of aryl halides. Here, we analyze the suggested photochemical mechanism of this reaction, which employs perylenediimide (PDI) as a photocatalyst, on the basis of spectroscopic, electrochemical and electron paramagnetic resonance data. Our results indicate that the photoexcited PDI radical anion (*PDI˙-) cannot play the role of a photosensitizer in the aforementioned process. Instead, the reduction of 4'-bromoacetophenone likely involves *PDI˙- decomposition products. The extremely short lifetime of the photoexcited transient species, as *PDI˙-, is a major general limitation for photocatalytic schemes based on sequential two-photon excitation. In order to better understand the potential of such schemes, we discuss them in the context of the Z-scheme in natural photosynthesis.

9.
Chemistry ; 24(5): 1198-1203, 2018 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-29125653

RESUMO

The synthesis of the new nitroxide crown ether 8 and its use as the wheel in a bistable [2]rotaxane, containing dialkylammonium and 4,4'-bipyridinium recognition sites, is reported. The synthesis of 8 was achieved by the sequential addition of substituted phenyl groups to a nitrone derivatives leading to the preferential formation of the cis stereoisomer. Due to charge-dipole interactions between the nitroxide unit and the bipyridinium moiety, it was possible to probe the movement of the macrocycle between the two molecular stations of the [2]rotaxane after addition of a base by measuring the nitrogen hyperfine splitting in the corresponding EPR spectra. The equilibrium constant for the complexation of dibenzyl viologen by the macrocycle 8 was also determined by EPR titration.

10.
Proc Natl Acad Sci U S A ; 115(38): 9385-9390, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-29255033

RESUMO

Allosteric control, one of Nature's most effective ways to regulate functions in biomolecular machinery, involves the transfer of information between distant sites. The mechanistic details of such a transfer are still an object of intensive investigation and debate, and the idea that intramolecular communication could be enabled by dynamic processes is gaining attention as a complement to traditional explanations. Mechanically interlocked molecules, owing to the particular kind of connection between their components and the resulting dynamic behavior, are attractive systems to investigate allosteric mechanisms and exploit them to develop functionalities with artificial species. We show that the pKa of an ammonium site located on the axle component of a [2]rotaxane can be reversibly modulated by changing the affinity of a remote recognition site for the interlocked crown ether ring through electrochemical stimulation. The use of a reversible ternary redox switch enables us to set the pKa to three different values, encompassing more than seven units. Our results demonstrate that in the axle the two sites do not communicate, and that in the rotaxane the transfer of information between them is made possible by the shuttling of the ring, that is, by a dynamic intramolecular process. The investigated coupling of electron- and proton-transfer reactions is reminiscent of the operation of the protein complex I of the respiratory chain.


Assuntos
Técnicas Eletroquímicas/métodos , Modelos Químicos , Conformação Molecular , Rotaxanos/química , Sítios de Ligação , Estimulação Elétrica , Transporte de Elétrons , Transferência de Energia , Estrutura Molecular , Prótons
11.
Sci Rep ; 7(1): 2028, 2017 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-28515485

RESUMO

Electronic cigarettes (e-cigs) are devices designed to deliver nicotine in a vaping solution rather than smoke and without tobacco combustion. Perceived as a safer alternative to conventional cigarettes, e-cigs are aggressively marketed as lifestyle-choice consumables, thanks to few restrictions and a lack of regulatory guidelines. E-cigs have also gained popularity among never-smokers and teenagers, becoming an emergent public health issue. Despite the burgeoning worldwide consumption of e-cigs, their safety remains largely unproven and it is unknown whether these devices cause in vivo toxicological effects that could contribute to cancer. Here we demonstrate the co-mutagenic and cancer-initiating effects of e-cig vapour in a rat lung model. We found that e-cigs have a powerful booster effect on phase-I carcinogen-bioactivating enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), and increase oxygen free radical production and DNA oxidation to 8-hydroxy-2'-deoxyguanosine. Furthermore, we found that e-cigs damage DNA not only at chromosomal level in peripheral blood, such as strand breaks in leucocytes and micronuclei formation in reticulocytes, but also at gene level such as point mutations in urine. Our results demonstrate that exposure to e-cigs could endanger human health, particularly among younger more vulnerable consumers.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Neoplasias/etiologia , Neoplasias/metabolismo , Animais , Antioxidantes/metabolismo , Dano ao DNA , Cromatografia Gasosa-Espectrometria de Massas , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Neoplasias/patologia , Oxirredução , Ratos , Espécies Reativas de Oxigênio/metabolismo , Medição de Risco , Fatores de Risco , Compostos Orgânicos Voláteis/efeitos adversos , Compostos Orgânicos Voláteis/análise
12.
J Org Chem ; 82(12): 6133-6141, 2017 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-28534620

RESUMO

A kinetic study of the hydrogen atom transfer (HAT) reactions from a series of organic compounds to the quinolinimide-N-oxyl radical (QINO) was performed in CH3CN. The HAT rate constants are significantly higher than those observed with the phthalimide-N-oxyl radical (PINO) as a result of enthalpic and polar effects due to the presence of the N-heteroaromatic ring in QINO. The relevance of polar effects is supported by theoretical calculations conducted for the reactions of the two N-oxyl radicals with toluene, which indicate that the HAT process is characterized by a significant degree of charge transfer permitted by the π-stacking that occurs between the toluene and the N-oxyl aromatic rings in the transition state structures. An increase in the HAT reactivity of QINO was observed in the presence of 0.15 M HClO4 and 0.15 M Mg(ClO4)2 due to the protonation or complexation with the Lewis acid of the pyridine nitrogen that leads to a further decrease in the electron density in the N-oxyl radical. These results fully support the use of N-hydroxyquinolinimide as a convenient substitute for N-hydroxyphthalimide in the catalytic aerobic oxidations of aliphatic hydrocarbons characterized by relatively high C-H bond dissociation energies.

13.
Chemistry ; 23(26): 6380-6390, 2017 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-28263437

RESUMO

A shape-persistent molecule, featuring four bipyridinium units, has been synthesized that upon reduction undergoes intermolecular pimerization because of the rigid architecture of the molecule. The pimerization process has been investigated by a variety of techniques, such as absorption measurements, EPR spectroscopy, as well as gamma and pulse radiolysis, and compared with the behavior of a model compound. Computational studies have also been performed to support the experimental data. The most interesting feature of the tetramer is that pimerization occurs only above a threshold concentration of monoreduced species, on the contrary to the model compound. Furthermore, there is an increase of the apparent pimerization constant by increasing the concentration of reduced bipyridinium units. These results have been interpreted by the fact that pimerization is favored in the tetrahedrally shaped molecule because of a cooperative mechanism. Each multiply reduced molecule can indeed undergo multiple intermolecular interactions that enhance the stabilization of the system, also leading to hierarchical supramolecular growth. The resulting supramolecular system formed by such intermolecular pimerization should exhibit a diamond-like structure, as suggested by a simplified modeling approach. The intermolecular nature of the pimerization process occurring in the tetramer has been demonstrated by measuring the corresponding bimolecular rate constant by pulsed radiolysis experiments.

14.
Chemistry ; 22(45): 16017-16021, 2016 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-27527710

RESUMO

The synthesis of 2,3,5,6-tetrafluoro-4-iodobenzyl tert-butyl nitroxide (2-I) and its use as spin probe for the detection of halogen-bond (XB) complexes by EPR is reported. Formation of a XB complex between 2-I and several XB acceptors was evidenced by a significant change in the value of the benzylic hyperfine splitting upon complexation. Thermodynamic parameters for the formation of XB complex with quinuclidine were obtained by recording EPR spectra in the temperature range 203-294 K. In addition, competitive experiments allowed for the measurement of the equilibrium constant of the XB complex with a chloride anion. The proposed procedure constitutes the first direct EPR methodology providing a reliable determination of the strength of the XB bond in solution.

15.
Chemistry ; 22(26): 8745-50, 2016 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-27123774

RESUMO

Gaining detailed information on the structural rearrangements associated with stimuli-induced molecular movements is of utmost importance for understanding the operation of molecular machines. Pulsed electron-electron double resonance (PELDOR) was employed to monitor the geometrical changes arising upon chemical switching of a [2]rotaxane that behaves as an acid-base-controlled molecular shuttle. To this aim, the rotaxane was endowed with stable nitroxide radical units in both the ring and axle components. The combination of PELDOR data and molecular dynamic calculations indicates that in the investigated rotaxane, the ring displacement along the axle, caused by the addition of a base, does not alter significantly the distance between the nitroxide labels, but it is accompanied by a profound change in the geometry adopted by the macrocycle.

16.
Life Sci ; 145: 166-73, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26702769

RESUMO

AIMS: A large meta-analysis of randomized clinical trials has seriously questioned chemoprevention based on vitamins including vitamin E (VE), and an increased risk for cancer among long-term users was actually seen. However, the mechanism underlying these findings still remain unknown. To clarify the mechanism, in an in vivo model we studied the putative disruption of redox homeostasis and the perturbation of carcinogen metabolizing enzymes determined by VE. MAIN METHODS: Male Sprague-Dawley rats were treated ip with either 100 or 200mg/kg b.w. daily for 7 or 14 consecutive days. Controls received vehicle only. Cytochrome P450 (CYP) content, CYP-reductase, CYP-linked monooxygenases, as well as phase-II and the antioxidant enzymes catalase and NAD(P)H: quinone reductase were investigated in both liver and kidney. Free radical species in tissue subcellular preparations were measured by electronic paramagnetic resonance (EPR) spectroscopy coupled to a radical probe technique. KEY FINDINGS: No substantial changes of hepatic xenobiotic metabolism enzymes were determined by VE. Conversely, a powerful booster effect of various renal phase-I carcinogen bioactivating enzymes at both dosages and observational times was recorded. While no relevant changes of post-oxidative phase-II reactions were found in the liver, a significant inactivating effect was caused by VE in renal tissues. Antioxidant enzymes were found mainly downregulated by the treatment. In the kidney, a marked free radical over-generation linked to CYP induction was observed. SIGNIFICANCE: This study proved that VE acts as a co-carcinogen and pro-oxidant agent. Such epigenetic mechanisms may contribute to explain the harmful outcomes observed in humans.


Assuntos
Anticarcinógenos/efeitos adversos , Carcinógenos/metabolismo , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Vitamina E/efeitos adversos , Animais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Rim/enzimologia , Rim/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Masculino , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Vitamina E/administração & dosagem , Vitamina E/farmacologia
17.
ChemistryOpen ; 4(1): 18-21, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25861565

RESUMO

An acid-base switchable molecular shuttle based on a [2]rotaxane, incorporating stable radical units in both the ring and dumbbell components, is reported. The [2]rotaxane comprises a dibenzo[24]crown-8 ring (DB24C8) interlocked with a dumbbell component that possesses a dialkylammonium (NH2 (+)) and a 4,4'-bipyridinium (BPY(2+)) recognition site. Deprotonation of the rotaxane NH2 (+) centers effects a quantitative displacement of the DB24C8 macroring to the BPY(2+) recognition site, a process that can be reversed by acid treatment. Interaction between stable 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) radicals connected to the ring and dumbbell components could be switched between noncoupled (three-line electron paramagnetic resonance (EPR) spectrum) and coupled (five-line EPR spectrum) upon displacement of the spin-labelled DB24C8 macroring. The complete base- and acid-induced switching cycle of the EPR pattern was repeated six times without an appreciable loss of signal, highlighting the reversibility of the process. Hence, this molecular machine is capable of switching on/off magnetic interactions by chemically driven reversible mechanical effects. A system of this kind represents an initial step towards a new generation of nanoscale magnetic switches that may be of interest for a variety of applications.

18.
ChemistryOpen ; 4(1): 2, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25870780

RESUMO

Invited for this months cover are the groups of Professors Marco Lucarini and Alberto Credi at the University of Bologna. The cover picture shows coupled and uncoupled states of a [2]rotaxane incorporating stable nitroxide radical units in both the ring and dumbbell components. Interaction between nitroxide radicals could be switched between noncoupled (three-line electron paramagnetic resonance (EPR) spectrum) and coupled (five-line EPR spectrum) upon deprotonation of the rotaxane NH2 (+) centers that effects a quantitative displacement of a dibenzocrown macroring to a 4,4'-bipyridinium recognition site. The complete base- and acid-induced switching cycle of the EPR pattern was repeated several times without an appreciable loss of signal, highlighting the reversibility of the process. Hence, this molecular machine is capable of switching on/off magnetic interactions by chemically driven reversible mechanical effects. For more details, see the Communication on p. 18 ff.

19.
Chemistry ; 21(7): 2775-9, 2015 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-25538046

RESUMO

The EPR properties of a novel triradical obtained by single-electron oxidation of a nitroxide-spin-labelled rotaxane containing a tetrathiafulvalene unit and cyclobis(paraquat-p-phenylene) ring is reported. Rotaxanation is proved to have a dramatic effect on through-space magnetic interactions between radical fragments. Analysis of the EPR spectra by a three-jump model, allowed us to obtain structural information on the interlocked structure.

20.
Histol Histopathol ; 30(6): 725-35, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25541725

RESUMO

The aim of the study was to evaluate the effects of the antioxidant N-acetylcysteine (NAC), added in freezing/thawing solutions, on reactive oxygen species (RRS) levels and on ovarian tissue preservation after cryopreservation. Ovarian samples from 10 subjects suffering from cancer diseases were cryopreserved using the slow freezing/rapid thawing standard protocol without or with NAC supplementation. RRS levels produced during cryopreservation were monitored by electron paramagnetic resonance (EPR) spectroscopy. The preservation of fresh ovarian tissue (t0), thawed tissue (t1 and t1 NAC) and thawed tissue maintained at 4°C for 2 hrs (t2 and t2 NAC) was analysed by light microscopy, transmission electron microscopy, Ki67 immunohistochemical and TUNEL analysis. It was possible to design a maximum peak for RRS production at t1, which slightly decreased at t2. NAC reduced the extent of RRS levels in cryopreserved ovarian tissues if compared with non-supplemented ones, although not restoring RRS production to baseline values. Comparative analysis between the two cryopreservation protocols showed that a better preservation of morphological characteristics, proliferation index and DNA integrity of ovarian tissue was obtained using NAC and no differences between t1NAC and t2NAC were observed. The employment of NAC during cryopreservation procedure could be an useful strategy for preserving the function of endogenous cellular systems. Nevertheless, further studies on the viability of thawed ovarian tissue are needed to support the feasibility of this approach in clinical settings.


Assuntos
Acetilcisteína/farmacologia , Criopreservação/métodos , Ovário/efeitos dos fármacos , Adolescente , Adulto , Feminino , Humanos , Ovário/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Adulto Jovem
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