New Singlet Oxygen Source and Trapping Reagent for Peroxide Intermediates

Application of newly-developed water-soluble singlet oxygen sources in the oxidation of biologically important compounds and the electron-transfer process involving singlet oxygen has been reviewed. Particularly, oxidation products of tryptophan by chemically generated singlet oxygen were compared to those obtained in dye-sensitizd photooxygenation. The usefulness of trimethylsilyl cyanide as a trapping reagent for dipolar peroxide intermediates has been demonstrated in the photooxygenation of N-methylindoles, 2-(methoxymethylene)adamantane and adamantylideneadamantane in aprotic solvents. Based on these trapping reactions mechanism of singlet oxygen reaction of electron-rich enol ethers and enamines is discussed in light of theoretical calculation.     

New Singlet Oxygen Source and Trapping Reagent for Peroxide Intermediates

Application of newly-developed water-soluble singlet oxygen sources in the oxidation of biologically important compounds and the electron-transfer process involving singlet oxygen has been reviewed. Particularly, oxidation products of tryptophan by chemically generated singlet oxygen were compared to those obtained in dye-sensitizd photooxygenation. The usefulness of trimethylsilyl cyanide as a trapping reagent for dipolar peroxide intermediates has been demonstrated in the photooxygenation of N-methylindoles, 2-(methoxymethylene)adamantane and adamantylideneadamantane in aprotic solvents. Based on these trapping reactions mechanism of singlet oxygen reaction of electron-rich enol ethers and enamines is discussed in light of theoretical calculation.     

Lignans by photo-oxidation of propenyl phenols.

Dimeric cyclic or acyclic lignan derivatives have been obtained from isoeugenol under light induced oxidations (mainly by MB-sensitized photooxygenation in water/CH(3)CN or di-tert-butyl peroxide photo-oxidation). Coniferyl alcohol gives lignans only under peroxide-mediated photo-oxidation while ferulic acid was unreactive under both conditions.     

Mechanism of photoregeneration of reduced porphyrin in the presence of oxygen

Photooxidation of reduced forms of porphyrines (IIH2) was studied. It has been shown that photooxidation of IIH2 is sensitized by initial porphyrine formed in the course of the reaction. Singlet oxygen serves as the basic oxidizer. It is also informed that the search of metastable states of photoreduced anion forms of the pigments by means of flashphotolysis turned to be unsuccessful.     

Reactivities of diphenylfuran (a singlet oxygen trap) with singlet oxygen and hydroxyl radical in aqueous systems.

It has been studied whether 2,5-diphenylfuran is a specific singlet oxygen trap in aqueous systems. With certain ¹O₂ generating systems (Rose Bengal photooxygenation and NaOClH₂O₂ systems) and·OH generating systems (Fenton's reagent and acetaldehyde-xanthine oxidase system), diphenylfuran was chiefly converted in all cases to cis-dibenzoyl-ethylene, but not to trans-dibenzoylethylene. Low but detectable conversion of diphenylfuran to a hydroperoxide, probably a distinct ¹O₂-derived reaction in aqueous media, was found only in the Rose Bengal photooxygenation system.     

Activation of Molecular Oxygen by Infrared Laser Radiation in Pigment-Free Aerobic Systems

With the goal of mimicking the mechanisms of the biological effects of low energy laser irradiation, we have shown that infrared low intensity laser radiation causes oxygenation of the chemical traps of singlet oxygen dissolved in organic media and water saturated by air at normal atmospheric pressure. The photooxygenation rate was directly proportional to the oxygen concentration and strongly inhibited by the singlet oxygen quenchers. The maximum of the photooxygenation action spectrum coincided with the maximum of the oxygen absorption band at 1270 nm. The data provide unambiguous evidence that photooxygenation is determined by the reactive singlet ¹_g state formed as a result of direct laser excitation of molecular oxygen. Hence, activation of oxygen caused by its direct photoexcitation may occur in natural systems.     

Novel spiroanellated 1,2,4-trioxanes with high in vitro antimalarial activities

A remarkable increase in antimalarial in vitro activity was achieved by integration of spiroadamantane motifs in 6-alkylidene 1,2,4-trioxanes 3a-h via diastereoselective photooxygenation of allylic alcohols and subsequent BF(3)-catalyzed peroxyacetalization with adamantanone to give the active compounds 3e-h.     

Problems Associated with Distinguishing between Singlet Oxygen and Electron Transfer Photooxygenation Reactions

In the introduction a review is given of the various methods available for probing the mechanism of photooxygenation reactions. To illustrate the methodology, some new results on the the photooxygenation of α-ketocarboxylic acids and esters is given in which it is shown that these compounds sensitise singlet oxygen formation but are relatively unreactive to this oxidising species. Alternative mechanistic schemes are proposed.     

Stereospecific synthesis of a new class of compounds: bis-homoconduritol-A, -D, and -F

Bis-homoconduritol derivatives with conduritol-A, -D, and -F structures have been synthesized starting from cyclooctatetraene. The photooxygenation of trans-7,8-dibromo- and cis-7,8-dichlorobicyclo[4.2.0]octa-2,4-dienes afforded the bicyclic endoperoxides. Reduction of the endoperoxides with thiourea followed by acetylation gave the corresponding diacetates. The KMnO(4) oxidation and epoxidation of the diacetates followed by acetylation gave the tetraacetates. Removal of the halides either with zinc-dust or Na-anthracene followed by the ammonolysis of tetraacetates afforded the bis-homoconduritol derivatives in high yield.     

Photo-oxygenation sensitized by dyes

This paper discusses the mechanism of photooxygenation reactions sensitized by dyes, such as: rose bengal, methylene blue, tetraphenylporphin and chlorophyll a. First it is shown more particularly that: the quantum yields of singlet oxygen O2(1 delta g) production gamma delta, and of intersystem crossing singlet S1-triplet T1, gamma is, are not always equal and that the possibilities gamma delta greater than or less than gamma is may occur or are observed; the processes S1 + O2(3 sigma)----T1 + O2(3 sigma) and T1 + O2(3 sigma)----S0 + O2(1 delta g) are mainly if not fully responsible for the quenching of the singlet and triplet excited states of the sensitizer by oxygen. Thereafter, clear indication is given of the considerable complication of the photooxygenation which may arise from particular properties of the investigated substrate A (or of other compounds present in the reaction medium) and which may result in a decrease of the oxygenation quantum yield phi O2. It is shown that this lowering of phi O2 is due to that of gamma delta and/or of phi A, (the probability that O2(1 delta g) yields an oxygenation product AO2) since phi O2 = gamma delta phi A. The latter effect can be induced by the quenching of singlet oxygen by the dye, a process which is quite general and which must be always taken into account in kinetic studies.     

Photooxygenation of 2′,4,4′-trihydroxychalcone: Identity with products from enzymic oxidation

The dioxetane derivative of 2′,4,4′-trihydroxychalcone, previously known as a product from peroxidase-catalysed oxidation, has now been detected in the dye-sensitized photooxygenation of the same chalcone and shown to be accountable for the host of other products formed.     

Induced chirality of binary aggregates of oppositely charged water-soluble porphyrins on DNA matrix

The induced chirality of achiral binary aggregates of meso-tetrakis(4-N-methylpyridyl)porphyrine (TMPyP) and meso-tetrakis(4-sulfonatophenyl)porphyrine (TPPS) on a deoxyribonucleic acid (DNA) matrix was investigated. Although the negatively charged TPPS did not show induced chirality in DNA solution due to the electrostatic repulsion, induced chirality was obtained through the addition of a positively charged TMPyP. It was confirmed that the induced chirality was due to the binary complex formation between TPPS and TMPyP on the DNA matrix. Moreover, the induced chirality depended on the relative molar ratio of TPPS to TMPyP (r) and the binding modes of the complex to DNA. When r<1, induced circular dichroism (CD) spectrum of the ternary complex was similar to that of intercalated TMPyP into DNA. For r=1, the induced CD spectrum showed a reversed biphasic signal due to the complex of TMPyP and TPPS stacking along the DNA surface. At a higher r value (>1), there was an induced CD signal at 482 nm attributed to a lateral shifted arrangement of heteroaggregate of TPPS and TMPyP on DNA matrix where TMPyP acted as a spacer to mediate the growth of heteroaggregates. Increasing the concentration of sodium chloride in the solution would favor the formation of the lateral shifted arrangement of heteroaggregate of TPPS and TMPyP. The resonance light scattering (RLS) spectra confirmed the above results. Analysis of the CD spectral changes in DNA conformation showed that during the binary complex formation of TPPS and TMPyP, the intercalated TMPyP could be 'pulled out' from the base pairs of DNA, which might be useful in gene therapy. A model was proposed to account for these observations.     

Novel allocolchicinoids with an eight membered B-ring: design, synthesis and inhibition of tubulin assembly

Several B-ring variations of O-methyl androbiphenyline (8), newly accessible from (-)-(M,7S)-colchicine via photooxygenation and subsequent endoperoxide-transformation, were synthesized and evaluated for their inhibitory effects on tubulin assembly in vitro. The amino-allocolchicinoid (9), a key compound in this study, was transformed to the highly potent ketone 10 and by oxidation with H2O2/Na2WO4 to a mixture of syn/anti-oximes, like 11 and 12. These could easily be transformed to hitherto unknown allocolchicinoids 13 and 14 with an eight membered B-ring lactam obtained via a Beckmann rearrangement. Surprisingly both do not notably affect tubulin assembly, despite obvious structural similarities with active analogues of the thiocolchicine- and azasteganacin-series.     

Stereoselective synthesis of new rac-quercitols containing hydroxymethyl groups as glucosidase inhibitors

Stereoselective and efficient synthesis of hydroxymethyl-substituted rac-quercitols (13–15) was achieved, starting from cis-furan (Kobayashi, 2008) with photooxygenation reaction, which is readily available by the reduction of cis-phtalic anhydride. α- and β-Glucosidase enzyme activity of the target molecules was evaluated and good inhibitor activity was seen. One- and two-dimensional NMR spectroscopy, IR spectroscopy and X-ray crystallography were utilized in the structure characterization of products.     

Control of erythroid differentiation: possible role of the transferrin cycle

A monoclonal antibody to the chicken transferrin receptor (JS-8) blocked temperature-induced and spontaneous differentiation of avian erythroid cells transformed by ts- and wt-retroviral oncogenes. In cells committed to differentiate, JS-8 caused an arrest at the erythroblast or early reticulocyte stage, followed by premature cell death, whereas proliferation of noncommitted erythroid cells or other hematopoietic cells remained unaffected. JS-8 had no effect on transferrin binding or internalization, but blocked subsequent receptor-recycling resulting in reduced iron uptake. Restoration of high intracellular iron levels neutralized the action of JS-8, whereas an inhibitor of porphyrine biosynthesis (4,6-dioxoheptanoic acid) closely mimicked the effect of JS-8. This suggests that erythroid differentiation might involve coordinate synthesis of erythrocyte proteins subject to regulation by hemin or hemoglobin.     

Photochemical DNA cleavage by novel water-soluble sulfonated dihydroxy phosphorus(V) tetrabenzotriazacorrole

The photosensitizing properties of a novel water-soluble phthalocyanine-like photosensitizer, sulfonated dihydroxy phosphorus(V) tetrabenzotriazacorrole {P(OH)(2)TBCS(n)}, have been reported. It is relevant for the use of this dye as photodynamic sensitizer. The compound exhibited significant photocleavage of supercoiled (SC) pUC19 DNA. The photooxygenation and photocleavage to DNA showed high efficiency in generating singlet oxygen.     

Photochemical investigation of the IR absorption bands of molecular oxygen in organic and aqueous environment

It is shown that the weak IR absorption bands corresponding to the forbidden triplet-singlet transitions in oxygen molecules can be reliably studied in air-saturated solvents under ambient conditions using measurements of the photooxygenation rates of singlet oxygen traps (1,3-diphenylisobenzofuran or uric acid) upon direct excitation of oxygen molecules by IR diode lasers. The best results were obtained from comparison of the oxygenation rates upon direct and photosensitized singlet oxygen excitation. In the present paper, this method was applied to estimation of the absorbance (A(ox)) and molar absorption coefficients (ε(ox)) corresponding to the oxygen absorption bands at 765 and 1273 nm in carbon tetrachloride, acetone, alcohols and water. In carbon tetrachloride, the band at 1073 nm was also investigated. Correlation of the obtained data with the luminescence spectra and radiative rate constants of singlet oxygen, contribution of oxygen dimols and biological significance of the studied effects are discussed.     

Novel naphthalimide hydroperoxide photonucleases: the role of thiocyclic-fused area and the difference in spectra, photochemistry and photobiological activity

Novel five- and six-membered thiocyclic-fused naphthalimide hydroperoxides (7, 8) as photonucleases were designed, synthesized via unusual isomerization in Pschorr cyclization and photooxygenation. The five-membered 7 was able to induce single-strand nicks in duplex DNA pH independently (7.0–8.5) at 0.5 μM under 366 nm, while the six-membered 8 could photonick the duplex DNA pH dependently (7.0–8.5) at 5 μM under 450 nm and showed ‘time-controlled’ photo-bioactivity. Their thiocycles and the angular conjugated plane have contributions to their binding affinity with DNA and photocleaving efficiency.     

The Ene Reaction of Singlet Oxygen with Olefins

The reactions of singlet oxygen (¹O₂) with cis and trans butenes-1,1,1-d₃, at—80°C in Freon-11, show a product isotope effect (k_H/k_D) of 1.38 and 1.25 respectively. Isomerization of the starting materials or formation of dioxetanes were not observed during the course of the photooxygenation. Together with the isotope effects on the reactions of tetramethylethylene-d₆ isomers with singlet oxygen, these results require the reversible formation of a perepoxide or charge transfer intermediate.     

Orally active 1,2,4-trioxepanes: synthesis and antimalarial activity of a series of 7-arylvinyl-1,2,4-trioxepanes against multidrug-resistant Plasmodium yoelii in Swiss mice

7-Arylvinyl-1,2,4-trioxepanes 7a-d, 8a-d, 9a-d, 10a-d, 11a-c, and 12a-c, prepared by photooxygenation of homoallylic alcohols 5a-d, were evaluated against multi-drug resistant Plasmodium yoelii nigeriensis in Swiss mice by oral and intramuscular routes. Trioxepane 11c, the most active compound of the series, showed more than 98% suppression of parsitaemia at 96 mg/kg by both oral and intramuscular routes. This is the first report on in vivo active 1,2,4-trioxepanes.