RESUMO
Triple-negative breast cancer (TNBC) is insensitive to target therapy for non-TNBC and needs novel drug discovery. Extracts of the traditional herb Boesenbergia plant in Southern Asia exhibit anticancer effects and contain novel bioactive compounds but merely show cytotoxicity. We recently isolated a new compound from B. stenophylla, stenophyllol B (StenB), but the impact and mechanism of its proliferation-modulating function on TNBC cells remain uninvestigated. This study aimed to assess the antiproliferative responses of StenB in TNBC cells and examine the drug safety in normal cells. StenB effectively suppressed the proliferation of TNBC cells rather than normal cells in terms of an ATP assay. This preferential antiproliferative function was alleviated by pretreating inhibitors for oxidative stress (N-acetylcysteine (NAC)) and apoptosis (Z-VAD-FMK). Accordingly, the oxidative-stress-related mechanisms were further assessed. StenB caused subG1 and G2/M accumulation but reduced the G1 phase in TNBC cells, while normal cells remained unchanged between the control and StenB treatments. The apoptosis behavior of TNBC cells was suppressed by StenB, whereas that of normal cells was not suppressed according to an annexin V assay. StenB-modulated apoptosis signaling, such as for caspases 3, 8, and 9, was more significantly activated in TNBC than in normal cells. StenB also caused oxidative stress in TNBC cells but not in normal cells according to a flow cytometry assay monitoring reactive oxygen species, mitochondrial superoxide, and their membrane potential. StenB induced greater DNA damage responses (γH2AX and 8-hydroxy-2-deoxyguanosine) in TNBC than in normal cells. All these StenB responses were alleviated by NAC pretreatment. Collectively, StenB modulated oxidative stress responses, leading to the antiproliferation of TNBC cells with little cytotoxicity in normal cells.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Dano ao DNA , Proliferação de Células , Linhagem Celular Tumoral , Estresse Oxidativo , Apoptose , Acetilcisteína/farmacologiaRESUMO
Dendrimers are appealing scaffolds for creating carbohydrate mimics with unique multivalent cooperativity. We report here novel bola-amphiphilic glycodendrimers bearing mannose and glucose terminals, and a hydrophobic thioacetal core responsive to reactive oxygen species. The peculiar bola-amphiphilic feature enabled stronger binding to lectin compared to conventional amphiphiles. In addition, these dendrimers are able to target mannose receptors and glucose transporters expressed at the surface of cells, thus allowing effective and specific cellular uptake. This highlights their great promise for targeted delivery.
Assuntos
Dendrímeros , Manose , Manose/química , Dendrímeros/química , Espécies Reativas de Oxigênio , Carboidratos/química , Lectinas/química , GlucoseRESUMO
A rapid on-bead convergent method for preparing branched peptides was reported. Linear peptides were prepared on Dbz resin and ligated various branched cores, including lysine dendrons and other dendritic compounds. Alongside microwave irradiation, <1.5 equiv of peptides is sufficient to afford 50-65% yields of pure branched peptides without chromatographic purification. Remarkably, the desired compounds were prepared within hours.
Assuntos
Micro-Ondas , PeptídeosRESUMO
The reaction of iron(ii) and hydrogen peroxide, namely the Fenton reaction, is well-known for its strong oxidizing capability. While the Fenton reactions are ubiquitous and have wide applications in many areas, the detailed mechanism, especially the nature of the reactive intermediates responsible for oxidation, is not completely clear. In this work, the performances of various density functional theory (DFT) methods on the relative energies of key Fenton intermediates are evaluated. The DFT method selected from the benchmark study is then exploited to investigate the aqueous Fenton reactions in different pH conditions. The results show that at pH > 2.2, the major Fenton oxidants are high-valent oxoiron(iv) aquo complexes. However, depending on the pH conditions, these complexes can exist in three protonation states that display quite different oxidation reactivities. The oxidizing power of FeIV[double bond, length as m-dash]O is found to be principally determined by the total charge of the ligands and is less influenced by the axial ligand effect. Moreover, the calculations reveal that the presence of the hydronium ion can stabilize the intermediate of the hydroxyl radical and further inhibit oxoiron(iv) formation via proton transfer. The contribution of hydroxyl radicals could compete with the oxoiron(iv) species at pH below 2.2. In addition, high-level ab initio calculations question the existence of the iron(iv)-dihydroxo intermediate suggested in the literature. The implications of the computational results for the Fenton oxidation process, cytochrome P450, and catalyst design are discussed.
RESUMO
Here, this study overcomes the current barriers to efficient solid-phase synthesis of high-generation dendrimers by decreasing the loading ratio on the resin. G7 inverse poly(amidoamine) dendrimer is now prepared, for the first time, through a solid-phase synthesis using only 50% of the available reactive sites and by choosing a large resin. This preparation takes only 15 d to afford highly pure product in 80% yield with precipitation being the only purification procedure used. The results clearly show the amount of the initial monomer loaded on the resin to be a vital factor for the ability to use solid-phase synthesis to produce large dendrimers. This finding also sets stage for the applications of solid-phase synthesis for the preparation of other macromolecules.
Assuntos
Técnicas de Química Analítica/métodos , Dendrímeros/síntese química , Poliaminas/síntese química , Técnicas de Síntese em Fase SólidaRESUMO
Cisplatin, Pt(NH3)2Cl2, is a leading chemotherapeutic agent that has been widely used for various cancers. Recent experiments show that combining cisplatin and electron sources can dramatically enhance DNA damage and the cell-killing rate and, therefore, is a promising way to overcome the side effects and the resistance of cisplatin. However, the molecular mechanisms underlying this phenomenon are not clear yet. By using density functional theory calculations, we confirm that cisplatin can efficiently capture the prehydrated electrons and then undergo dissociation. The first electron attachment triggers a spontaneous departure of the chloride ion, forming a T-shaped [Pt(NH3)2Cl]Ë neutral radical, whereas the second electron attachment leads to a spontaneous departure of ammine, forming a linear [Pt(NH3)Cl](-) anion. We further recognize that the one-electron reduced product [Pt(NH3)2Cl]Ë is extremely harmful to DNA. It can abstract hydrogen atoms from the C-H bonds of the ribose moiety and the methyl group of thymine, which in turn leads to DNA strand breaks and cross-link lesions. The activation energies of these hydrogen abstraction reactions are relatively small compared to the hydrolysis of cisplatin, a prerequisite step in the normal mechanism of action of cisplatin. These results rationalize the improved cytotoxicity of cisplatin by supplying electrons. Although the biological effects of the two-electron reduced product [Pt(NH3)Cl](-) are not clear at this stage, our calculations indicate that it might be protonated by the surrounding water.
Assuntos
Cisplatino/química , Elétrons , Teoria Quântica , Cisplatino/farmacologia , DNA/química , DNA/efeitos dos fármacos , Dano ao DNARESUMO
Bioimaging is a powerful tool for diagnosing tumors but remains limited in terms of sensitivity and specificity. Nanotechnology-based imaging probes able to accommodate abundant imaging units with different imaging modalities are particularly promising for overcoming these limitations. In addition, the nanosized imaging agents can specifically increase the contrast of tumors by exploiting the enhanced permeability and retention effect. A proof-of-concept study is performed on pancreatic cancer to demonstrate the use of modular amphiphilic dendrimer-based nanoprobes for magnetic resonance (MR) imaging (MRI) or MR/near-infrared fluorescence (NIRF) multimodality imaging. Specifically, the self-assembly of an amphiphilic dendrimer bearing multiple Gd3+ units at its terminals, generates a nanomicellar agent exhibiting favorable relaxivity for MRI with a good safety profile. MRI reveals an up to two-fold higher contrast enhancement in tumors than in normal muscle. Encapsulating the NIRF dye within the core of the nanoprobe yields an MR/NIRF bimodal imaging agent for tumor detection that is efficient both for MRI, at Gd3+ concentrations 1/10 the standard clinical dose, and for NIRF imaging, allowing over two-fold stronger fluorescence intensities. These self-assembling dendrimer nanosystems thus constitute effective probes for MRI and MR/NIRF multimodality imaging, offering a promising nanotechnology platform for elaborating multimodality imaging probes in biomedical applications.
Assuntos
Dendrímeros , Neoplasias Pancreáticas , Humanos , Meios de Contraste , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Neoplasias Pancreáticas/diagnóstico por imagemRESUMO
The Ru(II)-nitrite complex, Ru4, is explored to release nitric oxide (NO) under acidic conditions and selectively induce a cytotoxic effect towards SK-MEL-28 cisplatin-resistant malignant melanoma cells. These findings suggest that targeting the tumor-associated pHe level could be an effective strategy for the drug function of Ru(II)-nitrite compounds.
Assuntos
Antineoplásicos , Cisplatino , Complexos de Coordenação , Cimenos , Resistencia a Medicamentos Antineoplásicos , Melanoma , Óxido Nítrico , Nitritos , Rutênio , Cisplatino/farmacologia , Cisplatino/química , Humanos , Rutênio/química , Rutênio/farmacologia , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Cimenos/farmacologia , Cimenos/química , Nitritos/química , Nitritos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Linhagem Celular Tumoral , Óxido Nítrico/metabolismo , Monoterpenos/farmacologia , Monoterpenos/química , Morte Celular/efeitos dos fármacosRESUMO
A one-step method for synthesizing 3-(Fmoc-amino acid)-3,4-diaminobenzoic acids was used to prepare preloaded diaminobenzoate resin. The coupling of free diaminobenzoic acid and Fmoc-amino acids gave pure products in 40-94% yield without any purification step in addition to precipitation except for histidine. For the proline residue, crude products were collected and used for solid-phase peptide synthesis to give a moderate yield of a pentapeptide. In addition, this method was used to prepare unusual amino acid derivatives, namely, (2-naphthyl) alanine and 6-aminohexanoic acid derivatives, in 50 and 65% yield, respectively.
RESUMO
The new copper(I) nitro complex [(Ph(3)P)(2)N][Cu(HB(3,5-Me(2)Pz)(3))(NO(2))] (2), containing the anionic hydrotris(3,5-dimethylpyrazolyl)borate ligand, was synthesized, and its structural features were probed using X-ray crystallography. Complex 2 was found to cocrystallize with a water molecule, and X-ray crystallographic analysis showed that the resulting molecule had the structure [(Ph(3)P)(2)N][Cu(HB(3,5-Me(2)Pz)(3))(NO(2))]·H(2)O (3), containing a water hydrogen bonded to an oxygen of the nitrite moiety. This complex represents the first example in the solid state of an analogue of the nitrous acid intermediate (CuNO(2)H). A comparison of the nitrite reduction reactivity of the electron-rich ligand containing the CuNO(2) complex 2 with that of the known neutral ligand containing the CuNO(2) complex [Cu(HC(3,5-Me(2)Pz)(3))(NO(2))] (1) shows that reactivity is significantly influenced by the electron density around the copper and nitrite centers. The detailed mechanisms of nitrite reduction reactions of 1 and 2 with acetic acid were explored by using density functional theory calculations. Overall, the results of this effort show that synthetic models, based on neutral HC(3,5-Me(2)Pz)(3) and anionic [HB(3,5-Me(2)Pz)(3)](-) ligands, mimic the electronic influence of (His)(3) ligands in the environment of the type II copper center of copper nitrite reductases (Cu-NIRs).
Assuntos
Materiais Biomiméticos/química , Domínio Catalítico , Cobre/química , Nitrito Redutases/química , Nitrocompostos/química , Compostos Organometálicos/química , Pirazóis/química , Materiais Biomiméticos/síntese química , Ligantes , Modelos Moleculares , Conformação Molecular , Nitritos/química , Compostos Organometálicos/síntese química , Oxirredução , Teoria QuânticaRESUMO
Two new bisanthraquinones, glabraquinone A and B (1-2) were isolated from the root of Prismatomeris glabra (Korth.) Valeton. In addition to the new glabraquinones, six known anthraquinones, that is, 1-hydroxy-2-methoxy-6-methylanthraquinone (3), 1,2-dimethoxy-7-methylanthraquinone (4), lucidin (5), nordamnacanthal (6), damnacanthal (7) and 2-carboxaldehyde-3-hydroxyanthraquinone (8)) and an aromatic compound, that is, catechol diethyl ether (9) were isolated and characterized in this study. Compounds 1, 4 and 9 showed mild activity, reducing N2A cell viability to 77%, 82% and 77%, respectively, in anti-neuroblastoma assay.
RESUMO
An efficient solid-phase method has been reported to prepare well-defined lysine defect dendrimers. Using orthogonally protected lysine residues, pure G2 to G4 lysine defect dendrimers were prepared with 48-95% yields within 13 h. Remarkably, high-purity products were collected via precipitation without further purification steps. This method was applied to prepare a pair of 4-carboxyphenylboronic acid-decorated defect dendrimers (16 and 17), which possessed the same number of boronic acids. The binding affinity of 16, in which the ε-amines of G1 lysine are fractured, for glucose and sorbitol was 4 times that of 17. This investigation indicated the role of allocation and distribution of peripheries for the dendrimer's properties and activity.
RESUMO
Catalytic nitrite reductions by CuII complexes containing anionic Me2Tp, neutral Me2Tpm, or neutral iPrTIC ligands in the presence of L-ascorbic acid, which served as an electron donor and proton source, were investigated. The results showed that auxiliary ligands are important for copper-mediated catalytic nitrite reduction. Furthermore, the electronic effects of the ligand govern the nitrite reduction efficiency, which should be considered at two control points: one is the susceptibility of the LCuI-nitrite species to protonation and the other is the susceptibility of LCuII to reduction giving LCuI. In addition, an external strong acid leads to the production of nitrous acid, which may suggest that the reactivity of nitrous acid toward the LCuI species is a third control point.
Assuntos
Nitritos , Ácido Nitroso , Catálise , Cobre , Ligantes , OxirreduçãoRESUMO
ß-Diketiminato copper(II) L1CuCl-L4CuCl and their nitrite complexes L1Cu(O2N) and L2Cu(O2N) have been synthesized and characterized. X-ray analysis of the L1CuCl-L4CuCl complexes clearly reveals their mononuclear structure with a four-coordinated Cu(II) center bound by one chloride and three nitrogen atoms of unsymmetrical ß-diketiminato ligands. Cyclic voltametric analysis of the Cu(II) complexes shows that the length of the pyridyl arm controls the Cu(II)/Cu(I) redox process. DFT and EPR results confirm that the geometry of the Cu(II) complexes is also controlled by the length of the chelating pyridyl arm. The oxygen atom transfer nitrite reduction of the Cu(II) nitrite complexes leads to the formation of copper(I)-PPh3 and OîPPh3 which were confirmed by 1H and 31P NMR. The length of the pyridyl arm of the copper(II) nitrite complexes governs the NO-releasing ability. These findings illustrate the important bioinspired behaviour and NO generation from nitrite via oxygen atom transfer of the unsymmetrical ß-diketiminato copper(II) complexes as compared to symmetrical ß-diketiminato copper(II) complexes.
RESUMO
A number of 6-aryl-11-iminoindeno[1,2-c]quinoline derivatives were synthesized and evaluated for their antiproliferative activities. Among them, (E)-6-{4-[3-(dimethylamino)propoxy]phenyl}-2-fluoro-9-hydroxy-11H-indeno[1,2-c]quinolin-11-one O-3-(dimethylamino)propyl oxime (23a) was the most active, exhibited GI(50) values of 0.64, 0.39, 0.55, 0.67, and 0.65µM against the growth of Hep G2, Hep 3B, A549, H1299, and MDA-MB-231, respectively. Compound 23a inhibited the growth of hepatoma cell lines in a dose- and time-dependent manner. The proportion of cells was decreased in the G1 and accumulated in G2/M phase after 12h treatment of 23a, while the hypodiploid (sub-G0/G1 phase) cells increased. Further investigations have shown that 23a induced cell cycle arrest at G2/M phase and induce apoptosis via activation of p53, Bax, and caspase-8 which consequently cause cell death.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fase G1/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Quinolinas/síntese químicaRESUMO
The formation of base pair radical anions is closely related to many fascinating research fields in biology and chemistry such as radiation damage to DNA and electron transport in DNA. However, the relevant knowledge so far mainly comes from studies on isolated base pair radical anions, and their behavior in the DNA environment is less understood. In this study, we focus on how the nucleobase sequence affects the properties of the guanine-cytosine (GC) base pair radical anion. The energetic barrier and reaction energy for the proton transfer along the N(1)(G)-H···N(3)(C) hydrogen bond and the stability of GCË(-) (i.e., electron affinity of GC) embedded in different sequences of base-pair trimer were evaluated using density functional theory. The computational results demonstrated that the presence of neighboring base pairs has an important influence on the behavior of GCË(-) in the gas phase. The excess electron was found to be localized on the embedded GC and the charge leakage to neighboring base pairs was very minor in all of the investigated sequences. Accordingly, the sequence behavior of the proton-transfer reaction and the stability of GCË(-) is chiefly governed by electrostatic interactions with adjacent base pairs. However, the effect of base stacking, due to its electrostatic nature, is severely screened upon hydration, and thus, the sequence dependence of the properties of GCË(-) in aqueous environment becomes relatively weak and less than that observed in the gas phase. The effect of geometry relaxation associated with neighboring base pairs as well as the possibility of proton transfer along the N(2)(G)-H···O(2)(C) channel have also been investigated. The implications of the present findings to the electron transport and radiation damage of DNA are discussed.
Assuntos
Pareamento de Bases , Citosina/química , DNA/química , Guanina/química , Prótons , Sequência de Bases , DNA/genética , Elétrons , Radicais Livres/química , Gases/química , Ligação de Hidrogênio , Modelos Moleculares , Teoria Quântica , Água/químicaRESUMO
[Cu(Y)((G:2-6)-dendri-PAMAM-(Py)(n))](2Y+) complexes (3) were prepared, and their ability to generate oxygen radical anions was investigated. The maximum catalytic efficiency (k'(cat)/K(M)) was found to be 0.32 min(-1)·µM(-1), and a positive dendritic effect was observed. The saturated kinetics revealed that the improved catalytic efficiency resulted from an enhanced binding affinity toward molecular oxygen. FROM THE CLINICAL EDITOR: In this basic science study, the oxygen radical anion generating ability of specific copper complex of a pyridine-modified poly(amidoamine) dendrimer was investigated and reported in details.
Assuntos
Cobre/química , Dendrímeros/química , Dendrímeros/síntese química , Desoxirribonucleases/metabolismo , Poliaminas/química , Poliaminas/síntese química , Piridinas/química , Ânions , Catálise , Cinética , Oxigênio/química , Espectrofotometria UltravioletaRESUMO
Three Ru(II)-DMSO complexes (1-3) containing 2-(3-pyrazolyl)pyridine (PzPy), 2-pyrazol-3-ylfuran (PzO), or 2-pyrazol-3-ylthiophene (PzS) ligand, were synthesized and characterized. The monodentate coordination of the heterocyclic pyrazolyl ligand (PzPy) with Ru(II) ion via N atom was confirmed by single crystal X-ray diffraction. Complex 1 could be converted to the known η2-bidentate PzPy complex cis(Cl), cis(S)-[RuCl2(PzPy)(DMSO)2] (4) under reflux conditions. The mechanism underlying binding mode transformation was studied by 1H NMR spectroscopy and density functional theory (DFT) calculations. The binding abilities of the complexes (1-4) with calf-thymus (CT) DNA and bovine serum albumin (BSA) were investigated using spectroscopic and molecular docking techniques. Among the four Ru(II) complexes, complexes 1 and 3 inhibited the long-term proliferation of human breast cancer cells, whereas complexes 2 and 4 did not inhibit their proliferation to a considerable extent. Interestingly, complexes 1 and 3 did not induce significant cell death but rather attenuated the clonogenicity of breast cancer cells by upregulating reactive oxygen species (ROS), endoplasmic reticulum (ER) and autophagic stress.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Dimetil Sulfóxido/análogos & derivados , Dimetil Sulfóxido/farmacologia , Pirazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , DNA/metabolismo , Dimetil Sulfóxido/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Pirazóis/síntese química , Pirazóis/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rutênio/química , Soroalbumina Bovina/metabolismoRESUMO
In this study, we present density functional theory calculations on the properties of proton transfer and electron binding in isolated, mono-, di-, and pentahydrated 9-methylguanine:1-methylcytosine (mG:mC) base pair radical anions. It was found that the proton transfer in mG:mC(*-) is coupled to the interbase propeller-twisting and stretching motions, which cooperatively shorten the proton-transfer distance. Without the propeller-twisting motion, the interbase stretching will be hindered and the proton-transfer distance will become somewhat longer, which in turn, results in rising of the kinetic barrier for proton transfer. The monohydration can assist or resist the proton-transfer reaction, depending on the hydration sites. Inclusion of five water molecules in the first hydration shell around mG:mC(*-) only moderately lowers the proton-transfer barrier from 3.80 to 3.01 kcal mol(-1) and the reaction energy from -3.16 to -6.40 kcal mol(-1) due to the cancellation between opposite influences of H(2)O molecules. A further consideration of bulk hydration using a polarizable continuum model does not affect the proton-transfer energetics. In contrast, both the first hydration shell and bulk hydration were found to play important roles in stabilizing the excess electron in mG:mC; the adiabatic electron affinity of mG:mC increases from 0.302 to 0.645 eV upon inclusion of five water molecules in the first hydration shell, and further increases to 1.813 eV when the bulk hydration is considered. We noticed that the water molecule can enhance electron binding by direct interaction with the nucleobase that accommodates excess electron or through the indirect effect of tuning interbase hydrogen bonds. In addition, the microhydration effects on proton transfer and electron binding were found to be approximately additive.
Assuntos
Pareamento de Bases , Citosina/análogos & derivados , Guanina/análogos & derivados , Teoria Quântica , Água/química , Citosina/química , Elétrons , Radicais Livres/química , Guanina/química , PrótonsRESUMO
The electron-attachment-induced proton transfer in the guanine-cytosine (G:C) base pair is thought to be relevant to the issues of charge transport and radiation damage in DNA. However, our understanding on the reaction mainly comes from the data of isolated bases and base pairs, and the behavior of the reaction in the DNA duplex is not clear. In the present study, the proton-transfer reaction in reduced G:C stacks is investigated by quantum mechanical calculations with the aim to clarify how each environmental factor affects the proton transfer in G:C(*-). The calculations show that while the proton transfer in isolated G:C(*-) is exothermic with a small energetic barrier, it becomes endothermic with a considerably enhanced energetic barrier in G:C stacks. The substantial effect of G:C stacking is proved to originate from the electrostatic interactions between the dipole moments of outer G:C base pairs and the middle G:C(*-) base-pair radical anion; the extent of charge delocalization is very small and plays little role in affecting the proton transfer in G:C(*-). On the basis of the electrostatic model, the sequence dependence of the proton transfer in the ionized G:C base pair is predicted. In addition, the water molecules in the first hydration shell around G:C(*-) display a pronounced effect that facilitates the proton-transfer reaction; further consideration of bulk hydration only slightly lowers the energetic barrier and reaction energy. We also notice that the water arrangement around an embedded G:C(*-) is different from that around an isolated G:C(*-), which could result in a very different solvent effect on the energetics of the proton transfer. In contrast to the important influences of base stacking and hydration, the effects of sugar-phosphate backbone and counterions are found to be minor. Our calculations also reveal that a G:C base pair embedded in DNA is capable of accommodating two excess electrons only in bulk hydration; the resultant G(N1-H)(-):C(N3+H)(-) dianion is stable and exists long enough to lead to DNA damage. The combination of the present results with the previous findings in literature suggests that the behaviors of charge transport and low-energy electron-induced damage in DNA are highly susceptible to the hydration level.