Oxoketene-oxoketene, imidoylketene-imidoylketene and oxoketenimine-imidoylketene rearrangements. 1,3-shifts of phenyl groups

Dibenzoylketene 5 undergoes degenerate 1,3-shifts of the phenyl group between acyl and ketene carbon atoms, thus interconverting it with 6 and 7. This 1,3-shift takes place in the gas phase under flash vacuum thermolysis (FVT) conditions, but not in solution at 110-145 degrees C. Imidoyl(benzoyl)ketene 13 undergoes degenerate 1,3-shift of the phenyl group on FVT, thus interconverting it with 14, but the ketenimine isomer 15 is not formed, and none of these shifts take place in the solid state at 250 degrees C. Imidoyl(p-toluoyl)ketene 21 undergoes a 1,3-p-tolyl shift, interconverting it with ketene 22 but not with ketenimine 23. The imidoyl(p-toluoyl)ketene rotamer 25 cyclizes to 4-toluoyloxyquinoline 28 and 4-quinolone 29. The cyclization of imidoyl(benzoyl)ketene 13 to 4-benzoyloxyquinoline 18, and of 25 to 28 involves 1,3-C-to-O shifts of benzoyl (toluoyl) groups. Calculations of the transition states for the transformations at the B3LYP/6-31G** level of theory are in agreement with the observed reaction preferences.

Quinolactacins revisited: from lactams to imide and beyond

Chemical analysis of a solid phase fermentation of an Australian Penicillium citrinum strain has returned all known examples of a rare class of N-methyl quinolone lactams, quinolactacins A2 (1), B2 (2), C2 (3) and Al (4), together with the new quinolactacins B1 (5), C1 (6), D1 (7) and D2 (8), and the novel derivatives quinolonimide (9) and quinolonic acid (10). Complete stereostructures were assigned to all these compounds by detailed spectroscopic analysis and chemical interconversion. Carefully controlled and monitored decomposition studies have confirmed that quinolactacins readily undergo C-3 epimerization and oxidation, and under appropriate conditions convert to quinolonimide and quinolonic acid. Mechanisms for key transformations are proposed. The decomposition studies suggested that only quinolactacins A2 (1) and B2 (2) are genuine natural products, with all other isolated compounds being decomposition artefacts. Quinolactacins C1 (6), C2 (3), and the racemic mixture of quinolactacins D1/D2 (8/7) all displayed notable cytotoxic activity.

Aryliminopropadienone-C-amidoketenimine-amidinoketene-2-aminoquinolone cascades and the ynamine-isocyanate reaction

Imidoylketenes 11 and oxoketenimines 12 are generated by flash vacuum thermolysis of Meldrum's acid derivatives 9, pyrrolediones 17 and 18, and triazole 19 and are observed by IR spectroscopy. Ketenimine-3-carboxylic acid esters 12a are isolable at room temperature. Ketenes 11 and ketenimines 12 undergo rapid interconversion in the gas phase, and the ketenes cyclize to 4-quinolones 13. When using an amine leaving group in Meldrum's acid derivatives 9c, the major reaction products are aryliminopropadienones, ArN=C=C=C=O (15). The latter react with 1 equiv of nucleophile to produce ketenimines 12 and with 2 equiv to afford maIonic acid imide derivatives 16. N-Arylketenimine-C-carboxamides 12c cyclize to quinolones 13c via the transient amidinoketenes 11c at temperatures of 25-40 degrees C. This implies rapid interconversion of ketenes and ketenimines by a 1,3-shift of the dimethylamino group, even at room temperature. This interconversion explains previously poorly understood outcomes of the ynamine-isocyanate reaction. The solvent dependence of the tautomerism of 4-quinolones/4-quinolinols is discussed. Rotational barriers of NMe2 groups in amidoketenimines 12c and malonioc amides and amidines 16 (24) are reported.

Calculations on the end-group conformational barrier in carotenoids and a study of the bioavailability of xanthophyll esters in humans

The present study measures the increase in serum carotenoid concentration in 30 healthy individuals after supplementation with a low dose xanthophyll ester (3 and 6 mg of lutein equivalent/per day) when compared to a placebo. Serum levels of carotenoids were measured using HPLC and showed an increase in the concentration of lutein, zeaxanthin and four lutein metabolites proportional to dose. In order to further assess the importance of the end-group structure in carotenoids we have investigated the influence of the end-group type and functionality on the conformational energy barrier. We used the density functional method implemented on GAUSSIAN 98 to calculate the conformational energy curves for rotation of the P-ring or the E-ring relative to short polyene chains around the C6-C7 single bond. A large barrier is observed for the interconversion of conformers in the E-rings (8 kcal/mol) when compared to beta rings (2.3-3 kcal/mol).

Spatiotemporal control over the co-conformational switching in pH-responsive flavylium-based multistate pseudorotaxanes

A multistate molecular dyad containing flavylium and viologen units was synthesized and the pH dependent thermodynamics of the network completely characterized by a variety of spectroscopic techniques such as NMR, UV-vis and stopped-flow. The flavylium cation is only stable at acidic pH values. Above pH ≈ 5 the hydration of the flavylium leads to the formation of the hemiketal followed by ring-opening tautomerization to give the cis-chalcone. Finally, this last species isomerizes to give the trans-chalcone. For the present system only the flavylium cation and the trans-chalcone species could be detected as being thermodynamically stable. The hemiketal and the cis-chalcone are kinetic intermediates with negligible concentrations at the equilibrium. All stable species of the network were found to form 1 : 1 and 2 : 1 host : guest complexes with cucurbit[7]uril (CB7) with association constants in the ranges 10(5)-10(8) M(-1) and 10(3)-10(4) M(-1), respectively. The 1 : 1 complexes were particularly interesting to devise pH responsive bistable pseudorotaxanes: at basic pH values (≈12) the flavylium cation interconverts into the deprotonated trans-chalcone in a few minutes and under these conditions the CB7 wheel was found to be located around the viologen unit. A decrease in pH to values around 1 regenerates the flavylium cation in seconds and the macrocycle is translocated to the middle of the axle. On the other hand, if the pH is decreased to 6, the deprotonated trans-chalcone is neutralized to give a metastable species that evolves to the thermodynamically stable flavylium cation in ca. 20 hours. By taking advantage of the pH-dependent kinetics of the trans-chalcone/flavylium interconversion, spatiotemporal control of the molecular organization in pseudorotaxane systems can be achieved.

Speciation analysis of Arsenic in fish and rice samples using liquid chromatography-inductively coupled plasma mass spectrometry

Chemical speciation in foodstuffs is of uttermost importance since it is nowadays recognized that both toxicity and bioavailability of an element depend on the chemical form in which the element is present. Regarding arsenic, inorganic species are classified as carcinogenic while organic arsenic, such as arsenobetaine (AsB) or arsenocholine (AsC), is considered less toxic or even non-toxic. Coupling a High Performance Liquid Chromatographer (HPLC) with an Inductively Coupled Plasma Mass Spectrometer (ICP-MS) combines the power of separation of the first with the selectivity and sensitivity of the second. The present work aims at developing a method, using HPLC-ICP-MS technique, to identify and quantify the chemical species of arsenic present in two food matrices, rice and fish. Two extraction methods, ultrasound and microwave, and different settings were studied. The best method was chosen based on recovery percentages. To ensure that no interconversion of species was occurring, individual spikes of each species of arsenic were made in both matrices and recovery rates were calculated. To guaranty accurate results reference material BCR-627 TUNA FISH, containing certified values for AsB and DMA, was analyzed. Chromatographic separation was achieved using an anion exchange column, HAMILTON-PRP X-100, which allowed to separate the four arsenic species for which standards were available (AsB, dimethylarsenic (DMA), arsenite (AsIII), arsenate (AsV). The mobile phase was chosen based on scientific literature and adjusted to laboratory conditions. Different gradients were studied. As a result we verified that the arsenic species present in both matrices were not the same. While in fish 90% of the arsenic present was in the form of arsenobetaine, in rice 80% of arsenic was present as DMA and 20% as inorganic arsenic.

Factors affecting gut metabolism and bioavailabilty of orange juice flavanones in humans

Several studies have supported a beneficial role of dietary flavonoids in reducing the risk/progression of chronic diseases (including hypertension, cardiovascular disease, certain cancers, type-2-diabetes, cognitive dysfunction, age-related bone disease). Their beneficial properties are likely to be affected by their structure, distribution in foods, food matrix, life habits (physical activity). Most dietary polyphenols reach the colon where they are metabolized to phenolic acids by gut bacteria. Lack of knowledge of the factors affecting flavonoid metabolism and bioavailability hinders understanding of their health effects. Therefore, this thesis aimed to investigate the effect of factors on bioavailability and metabolism of dietary polyphenols from orange juices (OJ) in in vitro and in vivo studies. In chapter 3, the variability of orange juice polyphenolic content was assessed using in vitro models of the human gastrointestinal tract. Chapter 4 investigated the reduced urinary phenolic acids after OJ and yoghurt (Y) in humans compared to OJ alone using in vitro models of the human gut. In chapter 5, raftiline and glucose were tested for effects on metabolism of hesperidin (flavanone not OJ). In chapter 6, an intervention study of 4 weeks moderate intensity exercise determined whether exercise affected bioavailability and metabolism of OJ flavanones in healthy sedentary females. The studies in this thesis showed that food sources, food matrix and physical exercise may determine the significant variations in bioavailability and metabolism of flavonoids, seen in a number of studies. These factors could result in differences in bioactivity and bioefficacy of polyphenols, and need to be taken into account in further studies of the effects of flavanones on disease risk.

Bioactive compounds of citrus as health promoters

Citrus are a group of fruit species, quite heterogeneous in many aspects, including chemical composition of the fruit. Since ancient times, some citrus fruits were used to prevent and cure human diseases. In the recent decades, it has been demonstrated that fruits can actually help prevent and cure some diseases and above all, they are essential in a balanced diet. Citrus fruits, as one of the groups of fruit species, with greater importance in the world, have been studied for their effects on human health. Some species of citrus were referred as potential antioxidant based therapy for heart disease, cancer and inflammation. Fruit peels and seeds have also high antioxidant activity. The health benefits of citrus fruit have mainly been attributed to the high level of bioactive compounds, such as phenols (e.g., flavanone glycosides, hydroxycinnamic acids), carotenoids and vitamin C. These compounds are present in the fruit pulp and hence in the juice. But some bioactive compounds can be found in parts of the fruit which usually are not used for human food. The content of bioactive compounds depends on the species and cultivar, but also depends on the production system followed in the orchard. Citrus fruits, their derivatives and their by-products (peel, pulp and oil) are reach in different bioactive compounds and its maturity, postharvest and agroindustry processes influence their composition and concentration. The aim of this chapter was to review the main bioactive compounds of the different components of citrus and their relationship to health.

Identification of metabolites of kurarinone from Sophora flavescens Ait in rat urine by ultra-performance liquid chromatography with linear ion trap orbitrap mass spectrometry

Purpose: To study the in vivo metabolism of kurarinone, a lavandulyl flavanone which is a major constituent of Kushen and a marker compound with many biological activities, using ultra-performance liquid chromatography coupled with linear ion trap Orbitrap mass spectrometry (UPLC-LTQ-Orbitrap- MS). Methods: Six male Sprague-Dawley rats were randomly divided into two groups. First, kurarinone was suspended in 0.5 % carboxymethylcellulose sodium (CMC-Na) aqueous solution, and was given to rats (n = 3, 2 mL for each rat) orally at 50 mg/kg. A 2 mL aliquot of 0.5 % CMC-Na aqueous solution was administered to the rats in the control group. Next, urine samples were collected over 0-24 h after the oral administrations and all urine samples were pretreated by a solid phase extraction (SPE) method. Finally, all samples were analyzed by a UPLC-LTQ-Orbitrap mass spectrometry coupled with an electrospray ionization source (ESI) that was operated in the negative ionization mode. Results: A total of 11 metabolites, including the parent drug and 10 phase II metabolites in rat urine, were first detected and interpreted based on accurate mass measurement, fragment ions, and chromatographic retention times. The results were based on the assumption that kurarinone glucuronidation was the dominant metabolite that was excreted in rat urine. Conclusion: The results from this work indicate that kurarinone in vivo is typically transformed to nontoxic glucuronidation metabolites, and these findings may help to characterize the metabolic profile of kurarinone.