Theoretical study of the phototoxicity of naproxen and the active form of nabumetone

Density functional theory using the hybrid functional B3LYP has been employed in order to study the mechanisms of photoinduced decomposition of the closely related nonsteroidal anti-inflammatory drugs naproxen (NP) and 6-methoxy-2-naphthylacetic acid (MNAA; the active form of nabumetone). The photochemical properties and computed energies of various species obtained in this study show that both drugs dominate in their deprotonated forms at physiological pH. The deprotonated acids are unable to decarboxylate from their excited singlets; instead, they decarboxylate from their first excited triplet states with high efficiency, overcoming energy barriers less than 3 and 1 kcal/mol for MNAA and NP, respectively. The ultraviolet and visible spectra of the neutral, deprotonated, and decarboxylated moieties of MNAA and NP are more-or-less similar but with higher probabilites (oscillator strength) for the latter. This fact, as well as the higher reactivity of NP, is explained in terms of the electron-donating effect of the additional methyl group present in NP. Singlet oxygen, superoxide radical anion, and corresponding peroxyl radical species are expected to be formed in different steps throughout the proposed photodegradation pathways of both drugs, which give rise to their effects on biomolecules, for example, lipid peroxidation.     

Radical dynamics of puerarin as revealed by laser flash photolysis and spin density analysis

Puerarin, a C-glycoside of daidzein, forms upon direct photoexcitation in acetonitrile an excited-state with a lifetime of 4.2 micros assigned by oxygen quenching and sensitized formation of triplet zeaxanthin as a triplet and phenoxyl radicals of ms lifetime insensitive to oxygen and with spin density delocalized over the ACB isoflavonoid ring system, [ACB]*, as shown by laser flash photolysis and theoretical spin density calculations. Photoexcitation of A-ring 7-phenolate puerarin yields a [AC]* radical, which converts into the [ACB]* radical with a rate constant of 3.6 x 10(5) s(-1) in 5% methanolic acetonitrile in a process triggered by B-ring deprotonation (4'-phenol). For the 7-phenolate with the 4'-phenol derivatized to yield a propyl anisole, no rearrangement of the initially formed [AC]* radical was observed. With the A-ring phenol derivatized, the 7-propyl-4'-phenolate forms a radical with spin density delocalized over the CB ring system, [CB]*, together with a minor fraction of [ACB]* due to propyl radical dissociations confirmed by BDE-calculations. Dianionic puerarin forms initially the [ACB]* radical, which is converted into the [CB]* radical in a slower process (1.6 x 10(4) s(-1)) assigned to 7-methylation. The radical dynamics is discussed in relation to puerarin/carotenoid antioxidant synergism at water/lipid interphases.     

Theoretical studies of damage to 3'-uridine monophosphate induced by electron attachment

Low-energy electrons (LEE) are well known to induce nucleic acid damage. However, the damage mechanisms related to charge state and structural features remain to be explored in detail. In the present work, we have investigated the N1-glycosidic and C3'-O(P) bond ruptures of 3'-UMP (UMP=uridine monophosphate) and the protonated form 3'-UMPH with -1 and zero charge, respectively, based on hybrid density functional theory (DFT) B3 LYP together with the 6-31+G(d,p) basis set. The glycosidic bond breakage reactions of the 3'UMP and 3'UMPH electron adducts are exothermic in both cases, with barrier heights of 19-20 kcal mol(-1) upon inclusion of bulk solvation. The effects of the charge state on the phosphate group are marginal, but the C2'-OH group destabilizes the transition structure of glycosidic bond rupture of 3'-UMPH in the gas phase by approximately 5.0 kcal mol(-1). This is in contrast with the C3'-O(P) bond ruptures induced by LEE in which the charge state on the phosphate influences the barrier heights and reaction energies considerably. The barrier towards C3'-O(P) bond dissociation in the 3'UMP electron adduct is higher in the gas phase than the one corresponding to glycosidic bond rupture and is dramatically influenced by the C2'-OH group and bulk salvation, which decreases the barrier to 14.7 kcal mol(-1). For the C3'-O(P) bond rupture of the 3'UMPH electron adduct, the reaction is exothermic and the barrier is even lower, 8.2 kcal mol(-1), which is in agreement with recent results for 3'-dTMPH and 5'-dTMPH (dTMPH=deoxythymidine monophosphate). Both the Mulliken atomic charges and unpaired-spin distribution play significant roles in the reactions.     

Evaluation of ionization techniques for mass spectrometric detection of contact allergenic hydroperoxides formed by autoxidation of fragrance terpenes

Hydroperoxides formed by autoxidation of common fragrance terpenes are strong allergens and known to cause allergic contact dermatitis (ACD), a common skin disease caused by low molecular weight chemicals. Until now, no suitable methods for chemical analyses of monoterpene hydroperoxides have been available. Their thermolability prohibits the use of gas chromatography and their low UV-absorption properties do not promote sensitive analytical methods by liquid chromatography based on UV detection. In our study, we have investigated different liquid chromatography/mass spectrometry (LC/MS) ionization techniques, electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and atmospheric pressure photoionization (APPI), for detection of hydroperoxides from linalool and limonene.Flow injection analysis was used to evaluate the three different techniques to ionize the monoterpene hydroperoxides, linalool hydroperoxide and limonene hydroperoxide, by estimating the signal efficacy under experimental conditions for positive and negative ionization modes. The intensities for the species [M+H]+ and [M+H-H2O]+ in positive ionization mode and [M-H]- and [M-H-H2O]- in negative ionization mode were monitored. It was demonstrated that the mobile phase composition and instrumental parameters have major influences on the ionization efficiency of these compounds. ESI and APCI were both found to be appropriate as ionization techniques for detection of the two hydroperoxides. However, APPI was less suitable as ionization technique for the investigated hydroperoxides.     

How close can you get? Studies of ultrafast light-induced processes in ruthenium-[60] fullerene dyads with short pyrazolino and pyrrolidino links

Two pyrazoline- and one pyrrolidine-bridged Ru(II)bipyridine-[60]fullerene dyads have been prepared and studied by ultrafast time-resolved spectroscopy. A silver-assisted synthesis route, in which Ag(I) removes the chlorides from the precursor complex Ru(bpy) 2Cl 2 facilitates successful coordination of the [60]fullerene-substituted third ligand. Upon light excitation of the ruthenium moiety, the emission was strongly quenched by the fullerene. The main quenching mechanism is an exceptionally fast direct energy transfer ( k obs > 1 x 10 (12) s (-1) in the pyrazoline-bridged dyads), resulting in population of the lowest excited triplet state of fullerene. No evidence for electron transfer was found, despite the extraordinarily short donor-acceptor distance that could kinetically favor that process. The observations have implications on the ongoing development of devices built from Ru-polypyridyl complexes and nanostructured carbon, such as C 60 or nanotubes.     

Hydrogen abstraction from deoxyribose by a neighbouring uracil-5-yl radical

Hydrogen abstraction from the C1' and C2' positions of deoxyadenosine by a neighbouring uracil-5-yl radical in the 5'-AU*-3' DNA sequence is explored using DFT. This hydrogen abstraction is the first step in a sequence leading to single or double strand break in DNA. The uracil-5-yl radical can be the result of photolysis or low-energy electron (LEE) attachment. If the radical is produced by photolysis the neighbouring adenine will become a cation radical and if it is produced by LEE the adenine will remain neutral. The hydrogen abstraction reactions for both cases were investigated. It is concluded that it is possible for the uracil-5-yl to abstract hydrogen from C1' and C2'. When adenine is neutral there is a preference for the C1' site and when the adenine is a radical cation the C2' site is the preferred. If adenine is positively charged, the rate-limiting step when abstracting hydrogen from C1' is the formation of an intermediate crosslink between uracil and adenine. This crosslink might be avoided in dsDNA, making C1' the preferred site for abstraction.     

The potential in bioethanol production from waste fiber sludges in pulp mill-based biorefineries

Industrial production of bioethanol from fibers that are unusable for pulp production in pulp mills offers an approach to product diversification and more efficient exploitation of the raw material. In an attempt to utilize fibers flowing to the biological waste treatment, selected fiber sludges from three different pulp mills were collected, chemically analyzed, enzymatically hydrolyzed, and fermented for bioethanol production. Another aim was to produce solid residues with higher heat values than those of the original fiber sludges to gain a better fuel for combustion. The glucan content ranged between 32 and 66% of the dry matter. The lignin content varied considerably (1-25%), as did the content of wood extractives (0.2-5.8%). Hydrolysates obtained using enzymatic hydrolysis were found to be readily fermentable using Saccharomyces cerevisiae. Hydrolysis resulted in improved heat values compared with corresponding untreated fiber sludges. Oligomeric xylan fragments in the solid residue obtained after enzymatic hydrolysis were identified using matrix-assisted laser desorption ionization-time of flight and their potential as a new product of a pulp mill-based biorefinery is discussed.     

Structure-based engineering of strictosidine synthase: auxiliary for alkaloid libraries

The highly substrate-specific strictosidine synthase (EC 4.3.3.2) catalyzes the biological Pictet-Spengler condensation between tryptamine and secologanin, leading to the synthesis of about 2000 monoterpenoid indole alkaloids in higher plants. The crystal structure of Rauvolfia serpentina strictosidine synthase (STR1) in complex with strictosidine has been elucidated here, allowing the rational site-directed mutation of the active center of STR1 and resulting in modulation of its substrate acceptance. Here, we report on the rational redesign of STR1 by generation of a Val208Ala mutant, further describing the influence on substrate acceptance and the enzyme-catalyzed synthesis of 10-methyl- and 10-methoxystrictosidines. Based on the addition of strictosidine to a crude strictosidine glucosidase preparation from Catharanthus cells, a combined chemoenzymatic approach to generating large alkaloid libraries for future pharmacological screenings is presented.