Gama-Lactones from Iryanthera species

The structure of juruenolide, a constituent of Iryanthera juruensis and I. ulei is revised to (2S, 3R, 4S)-3-hydroxy-4-methyl-2-(19′-piperonyl-1′-n-nonadecyl)-butanolide. The compound is epimeric at C-3 of the γ-lactone unit with grandinolide [(2S, 3S, 4S)-3-hydroxy-4-methyl-2- (19′-phenyl-1′-n-nonadecyl)-butanolide] from I. grandis. An extract of I. juruensis contained additionally juruenolide-B [(4S)-4-methyl-2-(19′-piperonyl-1′-n-nonadec-7′-enyl)-but-2-enolide]. Analogous products with heptadecyl and pentadecyl side chains co-occur with the respective nonadecyl derivatives. © 1983.

The combined effect of acupuncture and Tanacetum parthenium on quality of life in women with headache: randomised study

Background The aim of the present study was to investigate the efficacy and tolerability of acupuncture (AC), Tanacetum (TAN) or combined treatment on quality of life in women with chronic migraine (CM). Methods A total of 69 women volunteers were randomly divided into 3 groups: AC, acupuncture administered in 20 sessions over 10 weeks (n=22); TAN, at 150 mg/day (n=23); and AC+TAN (n=23). The primary outcome was Short-Form 36 (SF-36) quality of life assessment score. Secondary outcomes included the Migraine Disability Assessment (MIDAS) and visual analogue scale (VAS) score experienced after randomisation. Results AC+TAN was statistically significantly more effective than AC or TAN alone in overall health-related quality of life (SF-36; p<0.05), on MIDAS score (-35.1 (10.6) AC vs -24.8 (11.7) TAN vs -42.5 (9.8) AC+TAN; p<0.05) and in reducing the mean score of pain on VAS (-5.6 (2.4) AC vs -3.7 (2.1) TAN vs -6.4 (3.1) AC+TAN; p<0.05). Conclusions The present work shows an improvement of the quality of life and better analgesic effect of acupuncture combined with TAN treatment on migraine pain in women when compared with acupuncture or TAN alone.

Bioconversion of Iodoacetophenones by Marine Fungi

Nine marine fungi (Aspergillus sclerotiorum CBMAI 849, Aspergillus sydowii Ce19, Beauveria felina CBMAI 738, Mucor racemosus CBMAI 847, Penicillium citrinum CBMAI 1186, Penicillium miczynskii Ce16, P. miczynskii Gc5, Penicillium oxalicum CBMAI 1185, and Trichoderma sp. Gc1) catalyzed the asymmetric bioconversion of iodoacetophenones 1-3 to corresponding iodophenylethanols 6-8. All the marine fungi produced exclusively (S)-ortho-iodophenylethanol 6 and (S)-meta-iodophenylethanol 7 in accordance to the Prelog rule. B. felina CBMAI 738, P. miczynskii Gc5, P. oxalicum CBMAI 1185, and Trichoderma sp. Gc1 produced (R)-para-iodophenylethanol 8 as product anti-Prelog. The bioconversion of para-iodoacetophenone 3 with whole cells of P. oxalicum CBMAI 1185 showed competitive reduction-oxidation reactions.

SEASONAL VARIATION OF THE MAJOR SECONDARY METABOLITES PRESENT IN THE EXTRACT OF Eremanthus mattogrossensis Less (Asteraceae: Vernonieae) LEAVES

The species Eremanthus mattogrossensis, known as "veludo do cerrado" (cerrado velvet), is native to the Brazilian Cerrado. Because the amount of metabolites present in plants may be influenced by biological and environmental factors, here we conducted an HPLC-DAD-MS/MS investigation of the metabolite concentrations found in the MeOH/H2O extract of the leaves of this species. The main compounds were identified and quantified, and the metabolites were grouped by chemical class (caffeoylquinic acids, flavonoids, and sesquiterpene lactone). Statistical analysis indicated a straight correlation between the quantity of metabolites and seasonality, suggesting that environmental properties elicit important metabolic responses.

SECONDARY METABOLITES FROM NUDIBRANCHS Tambja stegosauriformis, Hypselodoris lajenis AND Okenia zoobotryon AND FROM BRYOZOANS Zoobotryon verticillatum AND Bugula dentata FROM THE BRAZILIAN COASTLINE

SECONDARY METABOLITES FROM NUDIBRANCHS Tambja stegosauriformis, Hypselodoris lajenis AND Okenia zoobotryon AND FROM BRYOZOANS Zoobotryon verticillatum AND Bugula dentata FROM THE BRAZILIAN COASTLINE. The chemical investigation of the MeOH extract from the bryozoan B. dentata MeOH yielded tambjamines A (1), C (3), D (4), K (6), aldehyde 8 and the new tambjamine J1(9), while the extract of its predator, the nudibranch Tambja stegosauriformis, yielded tambjamines C and K, along with aldehyde 8. Furodisinin lactone (11) was isolated from the nudibranch Hypselodoris lajensis, a compound previously isolated from Dysidea sponges. The alkaloid 2,5,6-tribromo-N-methylgramine (12) was isolated from the nudibranch Okenia zoobotryon and from its prey, the bryozoan Zoobotryon verticillatum, the only source of 12 previously known.

Tellurium in organic synthesis: a general approach to buteno- and butanolides

The naturally occurring butanolides (-)-blastmycinolactol, (+)-blastmycinone, (-)-NFX-2, (+)-anti-mycinone as well as the four stereoisomers of the butenolide Acaterin were prepared in high enantiomeric purity using hydroxy-vinyl tellurides as starting materials. (C) 2012 Elsevier Ltd. All rights reserved.

Stereoselective Bioreduction of 1-(4-Methoxyphenyl)ethanone by Whole Cells of Marine-Derived Fungi

Nine strains of marine-derived fungi (Aspergillus sydowii Ce15, A. sydowii Ce19, Aspergillus sclerotiorum CBMAI 849, Bionectria sp. Ce5, Beauveria felina CBMAI 738, Cladosporium cladosporioides CBMAI 857, Mucor racemosus CBMAI 847, Penicillium citrinum CBMAI 1186, and Penicillium miczynskii Gc5) were screened, catalyzing the asymmetric bioreduction of 1-(4-methoxyphenyl) ethanone 1 to its corresponding 1-(4-methoxyphenyl) ethanol 2. A. sydowii Ce15 and Bionectria sp. Ce5 produced the enantiopure (R)-alcohol 2 (>99% ee) in accordance with the anti-Prelog rule and, the fungi B. felina CBMAI 738 (>99% ee) and P. citrinum CBMAI 1186 (69% ee) in accordance with the Prelog rule. Stereoselective bioreduction by whole cells of marine-derived fungi described by us is important for the production of new reductases from marine-derived fungi.

Further Withaphysalin Derivatives from Acnistus arborescens

Two new epimeric chlorinated withaphysalins, rel-(4 beta,5 beta,6 alpha,18S,22R)- and rel-(4 beta,5 beta,6 alpha,18R,22R)-6-chloro-18,20-epoxy-18-ethoxy-4,5-dihydroxy-1- oxowitha-2,24-diene-26,22-lactone (1 and 2 resp.), together with the new rel-(4 beta,5 beta,6a,18R,22R)-6-chloro-18,20-epoxy-4,5-dihydroxy-18-methoxy-1-oxowitha-2,24-diene-26,22-lactone (3) and rel-(3 beta,4 beta,5 beta,6 beta,18R,22R)-5,6:18,20-diepoxy-3,18-diethoxy-4-hydroxy-1-oxowith-24-ene-26,22-lactone (4) were isolated from the leaves of Acnistus arborescens and named withaphysalins TW, respectively. The final structures and the complete 1H- and 13C-NMR assignments of the three chlorowithaphysalins 13 were performed by means of HR-ESI-MS and 1D- and 2D-NMR experiments, including COSY, HSQC, and HMBC, beside comparison with spectral data of analogous compounds from the literature. The structure of 4 was also confirmed by means of a single-crystal X-ray diffraction analysis.

Topical anti-inflammatory activity of yacon leaf extracts

Smallanthus sonchifolius (Poepp.) H. Rob. , Asteraceae, known as yacon, is an herb that is traditionally used for the treatment of diabetes in folk medicine. However, recent studies have demonstrated that this plant has other interesting properties such as anti-microbial and anti-inflammatory actions. Thus, the purpose of this study was to evaluate the topical anti-inflammatory property of different extracts prepared from yacon leaves and analyze the role of different chemical classes in this activity. Three yacon leaf extracts were obtained: aqueous extract, where chlorogenic acid derivatives and sesquiterpene lactones were detected; leaf rinse extract, rich in sesquiterpene lactones; and polar extract, rich in chlorogenic acid derivatives. All the extracts exhibited anti-edematogenic activity in vivo (aqueous extract: 25.9% edema inhibition at 0.50 mg/ear; polar extract: 42.7% inhibition at 0.25 mg/ear; and leaf rinse extract: 44.1% inhibition at 0.25 mg/ear). The leaf rinse extract furnished the best results regarding neutrophil migration inhibition, and NO, TNF-? and PGE2 inhibition. These data indicate that both sesquiterpene lactones and chlorogenic acid derivatives contribute to the anti-inflammatory action, although sesquiterpene lactones seem to have more pronounced effects. In conclusion, yacon leaf extracts, particularly the sesquiterpene lactone-rich extract, has potential use as topical anti-inflammatory agent.

Seasonal variation of the major secondary metabolites present in the extract of Eremanthus mattogrossensis Less (Asteraceae: Vernonieae) leaves

The species Eremanthus mattogrossensis, known as "veludo do cerrado" (cerrado velvet), is native to the Brazilian Cerrado. Because the amount of metabolites present in plants may be influenced by biological and environmental factors, here we conducted an HPLC-DAD-MS/MS investigation of the metabolite concentrations found in the MeOH/H2O extract of the leaves of this species. The main compounds were identified and quantified, and the metabolites were grouped by chemical class (caffeoylquinic acids, flavonoids, and sesquiterpene lactone). Statistical analysis indicated a straight correlation between the quantity of metabolites and seasonality, suggesting that environmental properties elicit important metabolic responses.

Metabólitos secundários dos nudibrânquios Tambja stegosauriformis, Hypselodoris lajensis e Okenia zoobotryon e dos briozoários Zoobotryon verticillatum e Bugula dentata da costa do Brasil

The chemical investigation of the MeOH extract from the bryozoan B. dentata MeOH yielded tambjamines A (1), C (3), D (4), K (6), aldehyde 8 and the new tambjamine J1(9), while the extract of its predator, the nudibranch Tambja stegosauriformis, yielded tambjamines C and K, along with aldehyde 8. Furodisinin lactone (11) was isolated from the nudibranch Hypselodoris lajensis, a compound previously isolated from Dysidea sponges. The alkaloid 2,5,6-tribromo-N-methylgramine (12) was isolated from the nudibranch Okenia zoobotryon and from its prey, the bryozoan Zoobotryon verticillatum, the only source of 12 previously known.

Messa a punto di procedure per la semi-sintesi di composti ad attività antitumorale partendo da prodotti naturali. Studi di struttura-attività

Camptothecin, (CPT) is a pentacyclic alkaloid isolated for the first time from the Chinese tree Camptotheca acuminata, and which has soon attracted the attention of medicinal chemists and pharmacologists due to its promising anti-cancer activity against the most aggressive histo-types. So far, most of the synthesized camptothecin analogues are A and B ring modified compounds, which have been prepared via synthetic or semi-synthetic routes. To the best of our knowledge, a very limited number of C, D, or E ring modified analogues of CPT have been reported; moreover, the few derivatives known from the literature showed a reduced or no biological activity. This dissertation presents synthetic studies on camptothecin new derivatives along with the development of a new and general semi-synthetic methodology to obtain a large variety of analogues. We report here the semi-synthesis of a new family of 5-substituted CPT's, along with their biological activity evaluation, which will be compared with reference compounds. The use of carrier-linked prodrugs has emerged as a useful strategy to overcome some of the drawbacks related with the use of the parent drug, such as low solubility, membrane permeability properties, low oral absorption, instability, toxicity, and nontargeting. Herein we report CPT-prodrugs synthesized via ring opening of the lactone moiety as 17-O-acyl camptothecin tripartate conjugates, which bear a polyamine side chain with different architectures, as the carriers. Moreover, we found that the replacement of the oxygen atom with sulphur on the piridone D-ring, dramatically improves the potency of the novel 16a-thio-camptothecin derivatives, opening new possibilities in the modelling of this class of compounds.

New methods for the functionalization of metathesis polymers

Two general strategies for the functionalization of metathesis polymers are presented in this dissertation. Introducing Sacrificial Synthesis, many of the limitations of ruthenium-catalyzed ROMP have been overcome. Here, the living ROMP polymer to be functionalized was turned into a diblock copolymer by polymerizing dioxepine monomers onto the desired first polymer block. The second block was then later removed to leave “half-a-dioxepin”, i.e. exactly one hydroxyl group, at the chain-end. The efficiency of Sacrificial Synthesis is also studied. Thiol groups were also placed by a sacrificial strategy based on cyclic thioacetals. 2-Phenyl-1,3-dithiepin could be polymerized and subsequently cleaved by hydrogenation with Raney-Nickel. The presence of thiol groups on the chain end has been proven by chemical means (derivatization) and by coating gold-nanoparticles. The second strategy, vinyl lactone quenchingv is a termination reaction based on vinyl esters. After a metathesis step, an inactive Fischer-type carbene is formed. Such acyl carbenes are unstable and self-decompose to set an inactive ruthenium complex and the functional group free without changing the reaction conditions. The two compounds vinylene carbonate and 3H-furanone gave rise to the placement of aldehydes and carboxylic acids at the polymer chain ends without the necessity to perform any deprotection steps after the functionalization. The development of those two functionalization methods led to several applications. By reacting hydroxyl-functionalized ROMP-polymers with norbornene acid, macromonomers were formed which were subsequently polymerized to the respective graft-copolymers. Also, the derivatization of the same functionalized polymers with propargylic acid gave rise to alkyne-functionalized polymers which were conjugated with azides. Furthermore, “ugly stars”, i.e. long-chain branched structures were synthesized by polycondensation of ABn-type macromonomers and telechelic polymers were accessed combining the described functionalization techniques.

Der enzymatische und anti-oxidative Mechanismus des anti-atherogenen Enzyms Paraoxonase-2

Das humane Enzym PON2 ist in eine Vielzahl pathophysiologischer Prozesse involviert und ist durch zwei Funktionen gekennzeichnet - eine enzymatische Laktonase-Aktivität und eine anti-oxidative Aktivität. Durch die Laktonase-Aktivität hydrolysiert PON2 vorwiegend das bakterielle Signalmolekül 3oxoC12. PON2 ist als Bestandteil des angeborenen Immunsystems anzusehen und trägt wahrscheinlich zur Immunabwehr gegen Infektionen mit den human-pathogenen Pseudomonas aeruginosa Bakterien bei. Durch die anti-oxidative Aktivität vermindert PON2 oxidative Schäden und verringert redox-abhängige pro-apoptotische Stimulation. Diese einzigartige Funktion von PON2 ist jedoch ambivalent zu betrachten, da hohe PON2-Spiegel zwar Arteriosklerose reduzieren können, aber im Verdacht stehen Tumorzellen zu stabilisieren.rnIn dieser Arbeit wurden die noch unbekannten Mechanismen und der Zusammenhang der enzymatischen und der anti-oxidativen Aktivität analysiert. In diesem Rahmen wurde gezeigt, dass PON2 spezifisch die Superoxidfreisetzung an Komplex I und III der Atmungskette in der inneren Mitochondrienmembran reduzieren kann. PON2 veränderte dabei weder die Aktivitäten der Superoxiddismutasen noch die Cytochrom C-Expression. Weiterhin konnte in dieser Arbeit erstmals gezeigt werden, dass PON2 O2- nicht direkt abbaut, sondern vielmehr dessen Bildung verhindert. Diese Erkenntnisse implizieren, dass PON2 die anti-oxidative Aktivität über eine Beeinflussung des Quinon-Pools vermittelt. Anhand von verschiedenen Punktmutationen konnte gezeigt werden, dass die Histidinreste-114 und -133 für die Laktonase-Aktivität essentiell sind. Weiterhin wurden die Glykosylierungsstellen von PON2 identifiziert und gezeigt, dass die Glykosylierung, nicht aber der natürliche Polymorphismus Ser/Cys311 für die Laktonase-Aktivität von Bedeutung ist. Von besonderer Bedeutung ist, dass keine dieser Mutationen die anti-oxidative Aktivität beeinflusste, wodurch erstmals die Unabhängigkeit der beiden Funktionen von PON2 gezeigt werden konnte. rnEs war bekannt, dass PON2 gegen intrinsische und ER-Stress-induzierte Apoptose schützt. Die Spezifität der anti-oxidativen / anti-apoptotischen Wirkung wurde hier an einem weiteren pathophysiologischen Modell untersucht. 7-Ketocholesterol (7-KC) ist der Hauptbestandteil des pro-arteriosklerotischen oxLDL und verursacht in Zellen des Gefäßsystems ER-Stress, oxidativen Stress und Apoptose. Unerwarteterweise konnte PON2 Endothelzellen nicht gegen den 7-KC-induzierten Zelltod schützen. Mehrere unabhängige experimentelle Ansätze belegen, dass 7-KC in Endothelzellen im Gegensatz zu Gefäßmuskelzellen den Zelltod über Autophagie und nicht über ER-Stress oder intrinsische Apoptose bewirkt. Weiterhin führt 7-KC, wie auch 3oxoC12 und Thapsigargin zu einem Abbau der PON2-mRNA, die über die 5’UTR der PON2-mRNA vermittelt wird. Diese Arbeit vermittelt detaillierte mechanistische Einsichten in die Funktionen von PON2, die für ihre Rolle bei Arteriosklerose, in der körpereigenen Immunabwehr und bei Krebs entscheidend sind.rn

Synthese von Naturstoffen mit Lacton-Strukturen großer und mittlerer Ringgröße: Ein Curvularin-Analogon und Phomol

1.1 Synthese des dreizehngliedrigen (S)-(-)-Curvularin-AnalogonsrnAus biologischen Studien ist bekannt, dass (S)-(-)-Curvularin die Tyrosin-Phosphorylierung von STAT1-Proteinen inhibiert. Die Struktur des biologischen Targets ist jedoch unbekannt. Aus diesem Grund wurde eine Variation des (S)-(-)-Curvularin-Gerüsts vorgenommen werden, indem das zwölfgliedrige Ringgerüst erweitert wurde. Das dreizehngliedrigen (S)-(-)-Curvularin-Analogons konnte aus Acetondicarbonsäuredimethylester, (S)-Hex-5-en-2-ol, und Adipinsäuremonoallylester in 11 Stufen dargestellt werden.rn1.2 PhomolrnDas zweite Ziel dieser Arbeit war die Totalsynthese von Phomol. Zunächst wurden ausgehend von D Mannitol (3S,4R)-3,4-O-Isopropyliden-dec-1-en-5-ol in sechs Stufen und (3R,4R)-3,4-Dibenzyloxy-5-hexensäure in sieben Stufen synthetisiert und anschließend unter Yamaguchi-Bedingungen verestert. Die erhaltenen Ester wurden der Ringschlussmetathese unterworfen. Hierbei entstand das gewünschte Makrolacton lediglich in Spuren, welches spektroskopisch nachgewiesen werden konnten. Daher wurden im weiteren Verlauf (3S,4S,5S)-3-(p-Methoxybenzyl)-4-(triisopropylsilyloxy)-1-decen-5-ol und (3S,4S,5R)-3-(p-Methoxyben-zyl)-4-(triisopropylsilyloxy)-1-decen-5-ol in 10 Stufen aus (+) Xylose synthetisiert. Diese Alkohole wurden mit (3R,4R)-3,4-Di-p-methoxybenzyloxy-5-hexensäure, welche analog (3R,4R)-3,4-Dibenzyloxy-5-hexensäure dargestellt wurden, unter Yamaguchi-Bedingungen verestert und anschließend Studien zur Ringschlussmetathese unterworfen. Hierbei ließ sich nur ein Diastereomer zur Reaktion bringen wodurch sich (4R,5R,8S,9S,10R,E)-4,5,8-Tri(p-methoxybenzyloxy)-10-pentyl-9-(triisopropylsilyloxy)-3,3,5,8,9,10-hexahydro-2H-oxecin-2-on bildete. Nach Spaltung des Silylethers sollte die Seitenkette an C-8 eingeführt werden, was jedoch unter verschiedenen Bedingungen nicht gelungen ist. rnDas Grundgerüst des Phomols konnte in einer 20-stufigen Synthese ausgehend von D Mannitol und (+) Xylose aufgebaut werden. rn