Thermal Degradation of Small Molecules: A Global Metabolomic Investigation.

Thermal processes are widely used in small molecule chemical analysis and metabolomics for derivatization, vaporization, chromatography, and ionization, especially in gas chromatography mass spectrometry (GC/MS). In this study the effect of heating was examined on a set of 64 small molecule standards and, separately, on human plasma metabolite extracts. The samples, either derivatized or underivatized, were heated at three different temperatures (60, 100, and 250 °C) at different exposure times (30 s, 60 s, and 300 s). All the samples were analyzed by liquid chromatography coupled to electrospray ionization mass spectrometry (LC/MS) and the data processed by XCMS Online ( xcmsonline.scripps.edu ). The results showed that heating at an elevated temperature of 100 °C had an appreciable effect on both the underivatized and derivatized molecules, and heating at 250 °C created substantial changes in the profile. For example, over 40% of the molecular peaks were altered in the plasma metabolite analysis after heating (250 °C, 300s) with a significant formation of degradation and transformation products. The analysis of 64 small molecule standards validated the temperature-induced changes observed on the plasma metabolites, where most of the small molecules degraded at elevated temperatures even after minimal exposure times (30 s). For example, tri- and diorganophosphates (e.g., adenosine triphosphate and adenosine diphosphate) were readily degraded into a mono-organophosphate (e.g., adenosine monophosphate) during heating. Nucleosides and nucleotides (e.g., inosine and inosine monophosphate) were also found to be transformed into purine derivatives (e.g., hypoxanthine). A newly formed transformation product, oleoyl ethyl amide, was identified in both the underivatized and derivatized forms of the plasma extracts and small molecule standard mixture, and was likely generated from oleic acid. Overall these analyses show that small molecules and metabolites undergo significant time-sensitive alterations when exposed to elevated temperatures, especially those conditions that mimic sample preparation and analysis in GC/MS experiments.

Lamellarin D bioconjugates I: synthesis and cellular internalization of PEG-derivatives

Herein is reported the design and synthesis of poly(ethylene glycol) derivatives of Lamellarin D with the aim of modulating their physicochemical properties, and improving the biological activity. Mono-, di- and tri-PEG conjugates with improved solubility were obtained in 18-57% overall yields from the corresponding partially protected phenolic derivatives of Lamellarin D. Conjugates 1-9 were tested in a panel of three human tumor cell lines (MDA-MB-231 breast, A-549 lung and HT-29 colon) to evaluate their cytotoxicity. Several compounds exhibited enhanced cellular internalization, and more than 85% of the derivatives showed a lower GI50 than Lam-D. Furthermore, cell cycle arrest at G2 phase, and apoptotic cell-death pathways were determined for Lamellarin D and these derivatives.

Lamellarin D bioconjugates I: synthesis and cellular internalization of PEG-derivatives

Herein is reported the design and synthesis of poly(ethylene glycol) derivatives of Lamellarin D with the aim of modulating their physicochemical properties, and improving the biological activity. Mono-, di- and tri-PEG conjugates with improved solubility were obtained in 18-57% overall yields from the corresponding partially protected phenolic derivatives of Lamellarin D. Conjugates 1-9 were tested in a panel of three human tumor cell lines (MDA-MB-231 breast, A-549 lung and HT-29 colon) to evaluate their cytotoxicity. Several compounds exhibited enhanced cellular internalization, and more than 85% of the derivatives showed a lower GI50 than Lam-D. Furthermore, cell cycle arrest at G2 phase, and apoptotic cell-death pathways were determined for Lamellarin D and these derivatives.

Optimisation of the lipase-catalysed preparation of a nucleoside prodrug model using an experimental design methodology

The preparation of 2', 3'-di-O-hexanoyluridine (2) by a Candida antarctica B lipase-catalysed alcoholysis of 2', 3', 5'-tri-O-hexanoyluridine (1) was optimised using an experimental design. At 25 ºC better experimental conditions allowed an increase in the yield of 2 from 80% to 96%. In addition to the yield improvement, the volume reaction could be diminished in a factor of 5 and the reaction time significantly shortened.

Determinação espectrofotométrica simultânea de cobre e ferro em álcool etílico combustível com reagentes derivados da ferroína

In the present work three ferroin reagents were studied for the simultaneous spectrophotometric determination of iron and copper: 1,10-phenanthroline, 2,2'-bipyridine and 2,4,6-tri(2-pyridyl)-1,3,5-triazine. Effect of pH, conditions, order reagent addition, interferences, amount of reagents, lineal range, sensitivity and stability of each system were compared. The 2,4,6-tri(2-pyridyl)-1,3,5-triazine can be used for determination of iron in the presence of copper with a detection limit of 5 µg L-1 and coefficient of variation of 2.0%; However it was not possible to determine directly copper in the presence of iron with this reagent. 1,10-phenanthroline can be used for simultaneous determination of the metallic ions with detection limits of 7 and 8 mg L-1 and coefficients of variation of 1.8 and 2.3% in the determination of iron and copper, respectively. The results showed also that 2,2'-bipyridine can be used for simultaneous determination of the metallic ions with detection limits of 11 and 32 µg L-1 and coefficients of variation of 1.9 and 2.5% in the determination of iron and copper, respectively. The reagents were used for spectrophotometric determination of iron and copper in ethanol fuel.

Combine to compete: improving fiscal forecast accuracy over time

Budget forecasts have become increasingly important as a tool of fiscal management to influence expectations of bond markets and the public at large. The inherent difficulty in projecting macroeconomic variables – together with political bias – thwart the accuracy of budget forecasts. We improve accuracy by combining the forecasts of both private and public agencies for Italy over the period 1993-2012. A weighted combined forecast of the deficit/ ratio is superior to any single forecast. Deficits are hard to predict due to shifting economic conditions and political events. We test and compare predictive accuracy over time and although a weighted combined forecast is robust to breaks, there is no significant improvement over a simple RW model.

Combine to compete: improving fiscal forecast accuracy over time

Budget forecasts have become increasingly important as a tool of fiscal management to influence expectations of bond markets and the public at large. The inherent difficulty in projecting macroeconomic variables – together with political bias – thwart the accuracy of budget forecasts. We improve accuracy by combining the forecasts of both private and public agencies for Italy over the period 1993-2012. A weighted combined forecast of the deficit/ ratio is superior to any single forecast. Deficits are hard to predict due to shifting economic conditions and political events. We test and compare predictive accuracy over time and although a weighted combined forecast is robust to breaks, there is no significant improvement over a simple RW model.

Kapillaarielektroforeesin soveltaminen uuttofaasin koostumuksen analysointiin

Työn tarkoituksena oli löytää kapillaarielektroforeesimenetelmä (CE), joka soveltuisi metallien neste-nesteuutossa käytettävien orgaanisten uuttofaasien koostumuksen analysointiin. Kapillaarielektroforeesissa käytetyn elektrolyyttiliuoksen analyytti-kohtaista optimointia ei tässä työssä tehty, vaan liikkeelle lähdettiin fenoleille tarkoitetulla menetelmällä. Tarkasteltavia uuttoreagenssiryhmiä olivat hydroksi-oksiimit sekä fosfiinihappo- ja fosforihappopohjaiset reagenssit. Tutkittavia kaupallisia laimentimia olivat Orfom SX 11 ja Shellsol D70. Lisäksi tutkittiin kahta modifiointiainetta, TOPOa (tri-n-oktyylifosfiinioksidi) ja TXIB:tä (2,2,4-trimetyyli-1,3-pentaanidiolidi-isobutyraatti). Työssä tavoiteltiin kapillaarielektroforeesin hyötyjä erityisesti hydrometallurgisessa teollisuudessa. Suurimpana hyötynä ennakoitiin mahdollisuus analysoida suuria molekyylejä, kuten uuttoreagenssi-metallikomplekseja, joita ei pystytä analysoimaan kaasukromatografilla (GC). Näytteet voidaan myös analysoida ilman hidasta ja usein ei-kvantitatiivista derivatisointia. Kirjallisuudesta ei löytynyt aiempia artikkeleita CE:n soveltamisesta kyseisille aiheille. Kapillaarielektroforeesianalyyseissa pystyttiin esimerkiksi havaitsemaan hydroksi-oksiimin kuparikompleksi orgaanisessa faasissa. Seulonta-ajoissa yleisenä ongelmana oli kuitenkin tulosten heikko toistettavuus. Kapillaari-elektro-foreesi-menetelmä tarjoaa selvästi mahdollisuuksia tulevaisuudessa, mutta vielä sillä ei päästy luotettavaan toistoon sähkökentän häiriöiden ja elektrolyyttiliuoksen riittämättömän optimoinnin vuoksi. Lisäksi teollisissa olosuhteissa käytetyille autenttisille hydroksioksiimi- ja fosfiinihapponäytteille tehtiin perinteisiä kaasukromatografia-analyysejä, joiden perusteella voitiin nähdä uuttofaasin koostumuksen muuttuneen prosessissa. Hapettuminen sekä eri hydrolyysireaktiot ovat tärkeimmät syyt reagenssien ja laimentimien muuttumiselle. Näitä hajoamistuotteita ei tässä työssä onnistuttu analysoimaan kapillaarielektroforeesilla.

HPLC-ESI-MS/MS analysis of oxidized di-caffeoylquinic acids generated by metalloporphyrin-catalyzed reactions

This paper reports an HPLC-ESI-MS/MS investigation on the oxidation of 3,5- and 4,5- dicaffeoylquinic acid using iron(III) tetraphenylporphyrin chloride as catalyst. Two major mono-oxidised products of the quinic acid moiety have been identified for both compounds. However, only the 4,5-derivative afforded two different tri-oxo products. Thus, it seems that the oxidation pattern depends on the number and positions of the caffeic acid moieties present in caffeoylquinic acid molecules.

Diastereosseletividade na redução de enonas bicíclicas com hidretos volumosos

Reduction of five substituted octalones employing lithium tri-sec-butylborohydride (L-selectride®) in THF and ethyl ether led to allylic alcohols with moderate diastereoselectivity. The stereoselectivity of addition of bulky hydrides showed to be different from most examples in the literature and was strongly influenced by substitution on the octalone ring.

Constituintes químicos de Vernonia chalybaea mart.

The chemical investigation of the hexane and ethanol extracts from aerial parts of Vernonia chalybaea conducted to the isolation and characterization of a new aliphatic tetrahydroxyl ether, along with a series of known compounds such as 4 α,10 α-epoxyaromadendrane, friedelin, taraxasteryl acetate, pseudotaraxasteryl acetate, lupeyl acetate, lupeol, α-amiryn, β-amiryn, β-sitosterol, stigmasterol, 2,3-dimethyl-1,2,3-tri-hydroxybuthanol, angophorol, angophorol-7-O-glucoside, angophorol-7-O-rutinoside, 3,7-dimethoxy-5,3',4'-trihydroxyflavone and acacetin. The structures of all compounds were determined by spectroscopic analysis and comparison with published spectral data.

Estudo espectroscópico em elucidação estrutural de flavonoides de Solanum jabrense Agra & Nee e S. paludosum Moric

The NMR (RMN¹H, 13C, COSY, HMQC, HMBC, NOE-DIFF, NOESY) and mass spectra data analysis of sixteen flavonoids, including nine natural, 7-O-methylkanferol (ramnocitrin), 3,7-di-O-methylkanferol (kumatakenin), 3-O-methylquercetin, 3,7,3',4'-tetra-O-methylquercetin (retusin), 3,7,8,4'-tetra-O-methylgossipetin, 3,7,8,3',4'-penta-O-methylgossipetin, 7-O-methylapigenin (genkwanin), 3,7,8-tri-O-methylherbacetin, 7,4'- di-O-methylquercetin (ombuine), isolated from Solanum paludosum and S. jabrense, and seven prepared methyl and acetyl derivatives, are discussed according the substitution on the rings A, B and C.

Physico-chemical properties of meso-tetrakis(p-methoxyphenyl)porphyrin (TMPP) incorporated into pluronicTM p-123 and f-127 polymeric micelles

The physicochemical properties (solubilization, structural organization and stability) of meso-tetrakis(p-methoxyphenyl)porphyrin (TMPP), a promising photosensitizer for photodynamic therapy, solubilized in polymeric micelles of tri-block copolymers PluronicTM P-123 and F-127, were studied. The formulations obtained by the solid dispersion method led to monomerization of TMPP in these copolymers. Solubility studies showed that P-123 solubilizes double the photosensitizer than F-127. The self-aggregation phenomenon was affected by the [TMPP]/[poloxamer] ratio and medium temperature. The decrease in the temperature of these systems promoted the formation of different kinds of TMPP aggregates intrinsically connected with the structural changes occurring in the micelles.

DI-HIDROCUCURBITACINA B: SEMI-SÍNTESE DE NOVOS DERIVADOS GLICOSILADOS

In the last ten years, the interest in natural and semi-synthetic cucurbitacin derivatives has increased, primarily due their cytotoxic and anti-tumoral activities. However, the isolation of glycosylated cucurbitacins has been difficult due the presence of β-glucosidase enzyme. With the aim of obtaining new glycosylated derivatives, the glycosylation of dihydrocucurbitacin B under Köenigs-Knorr and imidate reaction conditions was studied. Novel glycoside derivatives 16-(1,2-orthoacetate-3,4,6-tri-O-acetyl-α-D-glucopyranosyl)-dihydrocucurbitacin B (2), 2-O-β-D-2,3,4,6-tetra-O-acetyl-galactopyranosyl dihydrocucurbitacin B (3) and 2-O-β-D-galactopyranosyl dihydrocucurbitacin B (4) were synthesized for the first time in 17% (2 and 3) and 48% (4) yields.