Endoperoxide Formation Research Articles

Benzoylation of Ergosterol through Nucleophilic Acyl Substitution and Subsequent Formation of Ergosterol Benzoate Endoperoxide by Reaction with Singlet Oxygen Generated by Photosensitization

Reactive oxygen species such as singlet oxygen have been a major focus of research in medicine. The effect of singlet oxygen on sterols within biological membranes is becoming increasingly more important. Ergosterol, a vitamin D precursor, is one such sterol. The benzoylation of ergosterol and subsequent reaction with singlet oxygen to form an endoperoxide provide two important reactions for the undergraduate laboratory. The benzoylation of ergosterol coordinates well with carboxylic acid chemistry generally covered in introductory organic chemistry. The photooxidation of ergosterol benzoate provides a unique dienophile for a [4 + 2] cycloaddition reaction. Singlet oxygen, generated by photosensitization, adds to the diene of the B ring of the sterol. Two explanations for the photosensitization are provided. The first explanation is for introductory organic chemistry students. The second explanation is for upper-level students and delves into electronic states and energy transfer. An optional microscale p...

ChemInform Abstract: Competitive Formation of Endoperoxide and Hydroperoxide in the Reaction of Singlet Oxygen with α-Terpinene.

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ChemInform Abstract: Endoperoxide Formation of Helianthrene with Triplet Molecular Oxygen. A Spin-Forbidden Reaction.

Dibenzo[a,o]perylene (helianthrene=HEL), known to be a very reactive singlet molecular oxygen ( 1 O 2 , 1 Δ g ) acceptor, also reacts with molecular oxygen in its triplet ground state ( 3 O 2 , 3 Σ g - ) to form helianthrene endoperoxide (HELPO). The thermal endoperoxide formation was studied in several solvents at room temperature

Evaluation of tea tree oil quality and ascaridole: A deep study by means of chiral and multi heart-cuts multidimensional gas chromatography system coupled to mass spectrometry detection

The natural-like assessment of essential oils is a demanding task due to the growing trend toward adulterations. Usually chiral chromatography was used for this purpose due to the capability of assessing stereospecificity which is directly related to the enzymatic pathways of each plant species. On the other hand, the quality of an essential oil involves also the evaluation of its oxidative state, mainly connected with the age and storage conditions. In fact, some modifications in the chemical profile of the oil can occur if not properly preserved. Alterations of the components due to oxidative reactions lead to the formation of peroxides, endoperoxides and epoxides, such as ascaridole and 1,2,4-trihydroxymenthane, usually present in very low amount, formed by the oxidation of terpinen-4-ol and α-terpinene, respectively. Therefore, in the present research, the quality of Australian Tea Tree oil ( Melaleuca alternifolia (Maiden & Betche) Cheel, Myrtaceae) was investigated by means of a multi heart-cut multidimensional gas chromatographic system coupled to a mass spectrometer detector and by conventional enantio-GC. The MDGC system allowed the complete separation of the compounds of interest transferred from the first column to a second dimension based on a different separation mechanism. The MS detector at the end of the second column provided the identification of the peaks with high similarity values because of their high purities after the multidimensional separation. Method validation was carried out, in order to use this procedure for routine application, monitoring the repeatability of 1D retention times and 2D peak areas, LoD and LoQ. Finally, enantiomeric ratios for chiral compounds were established to support quality data obtained.

Visible photostability of some ruthenium and platinum phthalocyanines in water and in the presence of organic substrates

Water-soluble, metal-tetrasubstituted phthalocyanines ( -SO3H , MPcS and -COOH , MPcC) of platinum and ruthenium were synthesized and their photostability to visible light irradiation was determined. For the ruthenium phthalocyanines, the characteristic visible Q band of the phthalocyanines was almost totally suppressed after five days of irradiation. The platinum derivatives were instead more resistant to photodegradation, and the Q band did not decrease by more than 25%. The addition of carbonyl compounds to the phthalocyanine solution in water (at concentrations at least 1400-fold those of the phthalocyanines) dramatically accelerated the photobleaching of these phthalocyanine complexes. PtPcS turned from blue to green and to colorless with one day of visible-light irradiation in the presence of acetone. This effect decreased with the increase in molecular weight of the ketones (from acetone to 2-pentanone). The addition of alcohols (i.e. 1-butanol) or other organics (i.e. phenylacetic acid) did not affect the photostability of these metal-tetrasubstituted phthalocyanines. Dioxygen also had an important role, as when the solutions of phthalocyanines were carefully deaerated before irradiation, the visible spectra were preserved. The platinum phthalocyanines, as with the palladium analogs, sensitize the photoproduction of 1O2 , as shown by the formation of endoperoxide and its rearranged products in the presence of furfuryl alcohol (a singlet oxygen trapping agent).

Self‐Sensitized Photooxygenation of a C60–Cycloheptatriene Dyad to Form Norcaradiene‐Derived Endoperoxides

AbstractThe [60]fullerene–cycloheptatriene dyad 1 readily underwent [4+2] cycloaddition of molecular oxygen at the cycloheptatriene moiety to give endoperoxides 5‐exo and 5‐endo. The involvement of singlet oxygen was verified by the complete inhibition of oxygenation on addition of 1,4‐diazabicyclo[2.2.2]octane (DABCO), which is an efficient singlet‐oxygen quencher. The observed facile oxygenation was attributed to both the strong photosensitizing ability of the fullerene cage and to the valence isomerization of 1 to the norcaradiene form, which was facilitated by the bulky tert‐butyl groups. Competitive oxygenation of 1 and a related cycloheptatriene lacking the fullerenyl group (2) resulted in the formation of endoperoxides of the two molecules in comparable yields. This result demonstrates that the cycloaddition is not an in‐cage reaction but occurs after the singlet oxygen has diffused from the solvent cage.

Photochemistry of Bacteriochlorophylls in Human Blood Plasma: 1. Pigment Stability and Light‐induced Modifications of Lipoproteins

Transmetalated derivatives of bacteriochlorophyll are promising sensitizers in photodynamic therapy. Protocols using short delay times between injection and irradiation cause interest in the photochemistry of these pigments in the blood. Using near-infrared irradiation where these pigments absorb strongly, we have studied the photochemistry of Zn- and Pd-bacteriopheophorbide (WST09), and of the highly polar taurinated Pd-derivative, WST11, in isolated fractions of human blood plasma. The stability of all pigments is increased in blood plasma, compared with monomeric solutions. Pd-bacteriopheophorbide is much more stable than the other two derivatives. It also has a higher capacity for inducing reactive oxygen species, yet the consumption of oxygen is comparable. There is furthermore evidence for photobleaching under anoxic conditions. The generation of hydroperoxides (ROOH) is faster with Pd- than with Zn-complexes; the formation of endoperoxides (ROOR'), measured as thiobarbituric acid reactive substances, is comparable with the two central metals. Formation of both ROOH and ROOR' is increased in low-density lipoproteins (LDL) compared with high-density lipoproteins (HDL), which is probably related to the higher concentration of target molecules in the former. In HDL, extensive cross-linking is induced among the apolipoproteins; judged from the electrophoretic mobility of LDL and HDL particles, there is also a gross structural change. Photosensitized cross-linking is much less pronounced with high-density proteins.

Reaction of Protonated Tyrosine with Electronically Excited Singlet Molecular Oxygen (a1Δg): An Experimental and Trajectory Study

Reaction of protonated tyrosine with the lowest electronically excited singlet state of molecular oxygen, (1)O(2) (a(1)Delta(g)), is reported over the center-of-mass collision energy (E(col)) range from 0.1 to 3.0 eV, using an electrospray-ionization, guided-ion-beam scattering instrument, in conjunction with ab initio electronic structure calculations and direct dynamics trajectory simulations. Only one product channel is observed, corresponding to generation of hydrogen peroxide via transfer of two hydrogen atoms from protonated tyrosine. Despite being exoergic, the reaction is in competition with physical quenching of (1)O(2) and is very inefficient. At low E(col), the reaction may be mediated by intermediate complexes and shows strong inhibition by collision energy. At high E(col), the reaction efficiency drops to approximately 1% and starts to have contribution from a direct mechanism. Quasi-classical trajectory simulations were performed to probe the mechanism at high collision energies. Analysis of trajectories shows that, at E(col) of 3.0 eV, a small fraction of hydrogen peroxide (25%) is produced via a direct, concerted mechanism where two hydrogen atoms are transferred simultaneously, but most hydrogen peroxide (75%) is formed by dissociation of hydroperoxide intermediates. According to ab initio calculations and trajectory simulations, collisions also lead to formation of various endoperoxides, and dissociation of endoperoxides may play a role in physical quenching of (1)O(2). The apparatus and experimental techniques are described in detail.

Isolation and structure determination of oxidative degradation products of atorvastatin

Methods were developed for the preparation and isolation of four oxidative degradation products of atorvastatin. ATV-FX1 was prepared in the alkaline acetonitrile solution of atorvastatin with the addition of hydrogen peroxide. The exposition of aqueous acetonitrile solution of atorvastatin to sunlight for several hours followed by the alkalization of the solution with potassium hydroxide to pH 8–9 gave ATV-FXA. By the acidification of the solution with phosphoric acid to pH 3 ATV-FXA1 and FXA2 were prepared. The isolation of oxidative degradation products was carried out on a reversed-phase chromatographic column Luna prep C18(2) 10 μm applying several separation steps. The liquid chromatography coupled with a mass spectrometer (LC-MS), high resolution MS (HR-MS), 1D and 2D NMR spectroscopy methods were applied for the structure elucidation. All degradants are due to the oxidation of the pyrrole ring. The most probable reaction mechanism is intermediate endoperoxide formation with subsequent rearrangement and nucleophilic attack by the 5-hydroxy group of the heptanoic fragment. ATV-FX1 is 4-[1b-(4-Fluoro-phenyl)-6-hydroxy-6-isopropyl-1a-phenyl-6a-phenylcarbamoyl-hexahydro-1,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid and has a molecular mass increased by two oxygen atoms with regard to atorvastatin. ATV-FXA is the regioisomeric compound, 4-[6-(4-Fluoro-phenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1a-phenylcarbamoyl-hexahydro-1,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid. Its descendants ATV-FXA1 and FXA2 appeared without the atorvastatin heptanoic fragment and are 3-(4-Fluoro-benzoyl)-2-isobutyryl-3-phenyl-oxirane-2-carboxylic acid phenylamide and 4-(4-Fluoro-phenyl)-2,4-dihydroxy-2-isopropyl-5-phenyl-3,6-dioxa-bicyclo[3.1.0]hexane-1-carboxylic acid phenylamide, respectively. Quantitative NMR spectroscopy was employed for the assay determination of isolated oxidative degradation products. The results obtained were used for the determination of the UV response factors relative to atorvastatin.

FtmOx1, a non-heme Fe(ii) and α-ketoglutarate-dependent dioxygenase, catalyses the endoperoxide formation of verruculogen in Aspergillus fumigatus

Verruculogen is a tremorgenic mycotoxin and contains an endoperoxide bond. In this study, we describe the cloning, overexpression and purification of a non-heme Fe(ii) and alpha-ketoglutarate-dependent dioxygenase FtmOx1 from Aspergillus fumigatus, which catalyses the conversion of fumitremorgin B to verruculogen by inserting an endoperoxide bond between two prenyl moieties. Incubation with (18)O(2)-enriched atmosphere demonstrated that both oxygen atoms of the endoperoxide bond are derived from one molecule of O(2). FtmOx1 is the first endoperoxide-forming non-heme Fe(ii) and alpha-ketoglutarate-dependent dioxygenase reported so far. A mechanism of FtmOx1-catalysed verruculogen formation is postulated and discussed.

Singlet oxygenation in microemulsion catalysed by vanadium chloroperoxidase

Non-ionic microemulsions compatible with the enzyme vanadium chloroperoxidase were designed to perform singlet oxygenation of apolar substrates. The media were based on mono- and polydisperse ethoxylated fatty alcohols (CiEj), octane and aqueous buffer. “Fish” diagrams were determined to identify the Winsor-boundaries and to formulate a monophasic Winsor IV microemulsion with a minimal surfactant concentration, ensuring less singlet oxygen (1O2) loss than in an aqueous system, thus creating a high oxygenation efficiency. The enzyme was shown to be fully stable in the microemulsion for at least 10h, converting H2O2 into a constant flow of 1O2 in the aqueous microdomains. Part of the 1O2 diffuses into the organic compartments prior to fast physical deactivation of 1O2 by water molecules. In the apolar domains 1O2 quantitatively converts the model substrate 9,10-dimethylanthracene into its corresponding endoperoxide. Near-IR chemiluminescence measurements confirm that the 1O2 signal in the microemulsion is higher than in simple aqueous buffer. In a well-stirred (water/octane) biphasic system endoperoxide formation is also observed but the conversion rate is much lower, most likely due to stronger physical quenching of 1O2.

Unexpected photo-initiated oxidation of antimony in (tetra- tert-butyl)phthalocyaninatoantimony(III) complex in the presence of singlet oxygen acceptors

The title complex cation, [Sb(tbpc)] + (where tbpc denotes tetra( tert-butyl)phthalocyaninate, C 48H 48N 8 2−), was gradually bleached under irradiation with visible light (900 > λ/nm > 600) in aerated nonaqueous solvents, such as CH 2Cl 2, CHCl 3, benzene, chlorobenzene. On the other hand, irradiation under the same conditions but in the presence of 1,3-diphenylisobenzofuran (DPBF) caused slow oxidation of [Sb(tbpc)] + to the corresponding antimony(V) derivatives, [Sb(tbpc)LL′] +, (L and L′ denote monoanionic axial ligands containing oxygen as the donor atom), which was monitored by optical absorption and ESI-MS spectra of the photolyzed solutions. Both the photobleaching and oxidation have efficiently been inhibited by preliminary addition of β-carotene in photolyzed solutions, indicating that photosensitization of singlet oxygen ( 1O 2) by [Sb(tbpc)] + itself is involved. The use of furans (except dibenzofuran) or oxazoles instead of DPBF gave rise to similar oxidation but not in the case of the other type 1O 2-acceptors, such as 9,10-diphenylanthracene, tetraphenylcyclopentadienone, or 2,3-dimethyl-2-butene, indicating that formation of ozonide-type endo-peroxide through 1,4-cycloaddition with 1O 2 is essential. Peroxides, such as EtOOH and H 2O 2, generated through nucleophilic attack to the ozonide by EtOH and H 2O (present in the solvent) respectively, are considered to oxidize [Sb(tbpc)] + to the antimony(V) species. Photochemistry of antimony–phthalocyanine complex has been studied for the first time of pnicogen derivatives of phthalocyanine.

Determination of oxygen permeability of polymers using in-situ photo-generated heptacene

Heptacene generated in-situ in a polymer matrix using a photochemical route undergoes oxidation with diffused oxygen leading to the formation of endoperoxides. We have found the high reactivity of heptacene, a linear poly(acene), toward molecular oxygen can be used to determine oxygen permeability of polymer films. The rate of disappearance of heptacene, due to oxidation, was found to be directly related to the oxygen permeability of the polymer. A simple spectroscopic method to estimate oxygen permeability of polymer films by monitoring the visible/near infra-red absorption of heptacene is described.

COX-2, Another Important Player in the Nitric Oxide–Endothelin Cross-Talk

See related article, pages 1439–1445 Traditionally, the role of the endothelium was thought to be primarily that of a selective barrier to the diffusion of macromolecules from the vessel lumen to the interstitial space. During the past 20 years, numerous additional roles for the endothelium have been defined such as regulation of vascular tone, modulation of inflammation, promotion as well as inhibition of vascular growth, and modulation of platelet aggregation and coagulation. Endothelial dysfunction is a characteristic feature of patients with cardiovascular risk factors such as hypercholesterolemia, hypertension, diabetes mellitus, and chronic smoking. More recent studies indicate that it may predict long-term atherosclerotic disease progression as well as cardiovascular event rate.1 There is a growing body of evidence that decreased endothelial bioavailability of nitric oxide (NO·) in particular attributable to increased production of reactive oxygen species, such as superoxide (O2·−), leads to an activation of the renin–angiotensin system,2,3 increased formation of cyclooxygenase (COX)-dependent vasoconstrictors,4 but also to increased expression of the most potent endogenous vasoconstrictor endothelin-1 (ET-1).5–9 Of the 4 active endothelins (ET-1 to ET-4) ET-1 is the predominant isoform in the cardiovascular system. ET-1 exerts its major cardiovascular effects through activation of 2 distinct G protein–coupled receptors, the ETA and ETB receptors. ETA receptors are found exclusively in smooth muscle cells. Endothelin-1 promotes vasoconstriction, mitogenesis, and thrombosis predominantly via binding to the ETA receptor. ETB receptors are localized to some extent in smooth muscle cells, but also in endothelial cells. Activation of ETB receptors has been demonstrated to cause the release of NO· and prostacyclin (PGI2).10,11 In normal states with p reserved vascular (endothelial) NO …

Cyclooxygenase-2-Derived Prostacyclin Confers Atheroprotection on Female Mice

Before menopause, women are relatively protected against cardiovascular disease. Although estrogen (E2) retards atherogenesis in animal models and improves endothelial function in women with hyperlipidemia, the mechanisms of atheroprotection remain to be defined completely. The prostaglandin PGI2 inhibits platelet activation, vascular smooth muscle contraction, leukocyte-endothelial cell interactions, and cholesteryl ester hydrolase. PGI2 analogs limit atherogenesis, and atherosclerotic lesions have a reduced ability to produce PGI2. Cyclooxygenase 2 (COX-2), expressed in vascular endothelial cells, catalyzes the formation of prostaglandin endoperoxide from arachidonic acid, and this subsequently is transformed to PgI2 in endothelial cells by the action of PGI 2 synthase. Selective COX-2 inhibitors retard the excretion of PGI2 metabolites. These mechanisms may be relevant to atheroprotection in women because E2 increases the expression of COX-2 in vascular tissues and promotes the in vitro production of PGI2. Male mice lacking low-density lipoprotein receptor (LDLR) developed atherosclerosis more rapidly than did females, despite the lack of differences in total plasma cholesterol or high-density lipoprotein cholesterol. Female mice lacking both PGI2 receptor and the LDLR developed more prominent aortic lesions than did LDLR-knockout females (ie, lacking the gene for the LDL receptor). This effect was not gene dose-dependent and was not apparent in male mice. Further observations indicated that PGI2 decreases the platelet activation that characterizes early atherogenesis in female mice. It appears that PGI2 serves as an antioxidant in female LDLR-knockout mice before atherogenesis and at its earliest stage. Adding hydrogen peroxide to cultured mouse aortic smooth muscle cells increased synthesis of PGI2 and lipid peroxidation. There was no change in the expression of COX-2. Peroxide increased reactive oxygen species, and this effect was augmented by the lack of PGI2 receptor expression. These observations suggest that the PGI2 receptor modulates oxidant stress under baseline conditions. Importantly, E2 stimulated COX-2 expression and PGI2 formation. These findings suggest that E2 receptor alpha-mediated COX-2 stimulation of PGI2 makes a substantial contribution to atheroprotection in female LDLR-knockout mice. It is possible that ongoing treatment of patients with selective COX-2 inhibitors might undermine protection from cardiovascular disease in premenopausal females.

Photooxidation of Methylnaphthalenes

Studies on the photooxidation of methyl-substituted aromatic hydrocarbons have revealed that whereas electron density is a determinant of endoperoxide formation, steric factors are most important in influencing the stability of the endoperoxide. Additional information on the energetics of the reactions and on the magnitude of the steric interactions was obtained using calculations at the B3LYP/6-311+G* level of theory.

Photochemistry of A1E, a retinoid with a conjugated pyridinium moiety: competition between pericyclic photooxygenation and pericyclization.

The photochemistry of the retinoid analogue A1E shows an oxygen and solvent dependence. Irradiation of A1E with visible light (lambda(irr) = 425 nm) in methanol solutions resulted in pericyclization to form pyridinium terpenoids. Although the quantum yield for this cyclization is low (approximately 10(-4)), nevertheless the photochemical transformation occurs with quantitative chemical yield with remarkable chemoselectivity and diastereoselectivity. Conversely, irradiation of A1E under the same irradiation conditions in air-saturated carbon tetrachloride or deuterated chloroform produced a cyclic 5,8-peroxide as the major product. Deuterium solvent effects, experiments utilizing endoperoxide, phosphorescence, and chemiluminescence quenching studies strongly support the involvement of singlet oxygen in the endoperoxide formation. It is proposed that, upon irradiation, in the presence of oxygen, A1E acts as a sensitizer for generation of singlet oxygen from triplet oxygen present in the solution; the singlet oxygen produced reacts with A1E to produce cyclic peroxide. Thus, the photochemistry of A1E is characterized by two competing reactions, cyclization and peroxide formation. The dominant reaction is determined by the concentration of oxygen, the concentration of A1E, and the lifetime of singlet oxygen in the solvent employed. If the lifetime of singlet oxygen in a given solvent is long enough, then oxidation (peroxide formation) is the major reaction. If the singlet oxygen produced is quenched by the protonated solvent molecules faster than singlet oxygen reacts with A1E, then cyclization dominates.

UV irradiation of arylidene-β-ionones in the presence of dioxygen: regioselective formation of stable endoperoxides

UV irradiation of ( E, E)-arylidene-β-ionones 1 leads to photoisomerization resulting in ( Z, E) arylidene-β-ionones 2 , which undergo electrocyclization to 1,7,7-trimethyl-3-( E-2′-arylethenyl)-2-oxabicyclo[4.4.0]deca-3,5-dienes 3 , and the latter in the excited state add regioselectively, involving only the electron-rich endocyclic diene, to molecular oxygen affording highly stable endoperoxides 6 .

Singlet oxygen-mediated protein oxidation: evidence for the formation of reactive side chain peroxides on tyrosine residues.

Singlet oxygen (1O2) is generated by a number of enzymes as well as by UV or visible light in the presence of a sensitizer and has been proposed as a damaging agent in a number of pathologies including cataract, sunburn, and skin cancers. Proteins, and Cys, Met, Trp, Tyr and His side chains in particular, are major targets for 1O2 as a result of their abundance and high rate constants for reaction. In this study it is shown that long-lived peroxides are formed on free Tyr, Tyr residues in peptides and proteins, and model compounds on exposure to 1O2 generated by both photochemical and chemical methods. The yield of these species is significantly enhanced in D2O and decreased by azide. Nuclear magnetic resonance and mass spectroscopic analysis of reaction mixtures, or materials separated by high-performance liquid chromatography, are consistent with the initial formation of an (undetected) endoperoxide that undergoes rapid ring-opening to give a hydroperoxide situated at the C1 ring-position (i.e. para to the phenolic group). In the presence of a free alpha-amino group (e.g. with free Tyr), rapid ring-closure occurs to give an indolic hydroperoxide that decays into the corresponding alcohol, 3a-hydroxy-6-oxo-2,3,3a,6,7,7a-hexahydro-1H-indole-2-carboxylic acid. Hydroperoxides that lack a free alpha-amino group (e.g. those formed on 3-(4-hydroxyphenyl)propionic acid, N-Ac-Tyr and Tyr-containing peptides) are longer-lived, with half-lives of hours to days. These species undergo slow decay at low temperatures to give the corresponding alcohol. Their rate of decay is enhanced at 37 degrees C, or on exposure to UV light or metal ions, and gives rise to reactive radicals, via cleavage of the peroxide bond. These radicals have been characterized by electron paramagnetic resonance spin trapping. These studies demonstrate that long-lived Tyr-derived peroxides are formed on proteins exposed to 1O2 and that these may promote damage to other targets via further radical generation.

Synthesis and photochemical transformations of an anthracene containing methacrylic copolymer

A new methacrylate monomer containing anthracene moiety connected with long flexible spacer was prepared and copolymerized with n-butyl methacrylate. It has been found that upon illumination in inert atmosphere photodimerization of the anthracene rings takes place to a considerable extend. The reverse decomposition of the photodimers by thermal treatment is also facilitated by the long flexible spacer. In ambient air the only photoreaction is endoperoxide formation.