Giovanni Vidari

Electrophilic Cyclopentenone Neuroprostanes Are Anti-inflammatory Mediators Formed from the Peroxidation of the ω-3 Polyunsaturated Fatty Acid Docosahexaenoic Acid

The ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) possesses potent anti-inflammatory properties and has shown therapeutic benefit in numerous inflammatory diseases. However, the molecular mechanisms of these anti-inflammatory properties are poorly understood. DHA is highly susceptible to peroxidation, which yields an array of potentially bioactive lipid species. One class of compounds are cyclopentenone neuroprostanes (A4/J4-NPs), which are highly reactive and similar in structure to anti-inflammatory cyclopentenone prostaglandins. Here we show that a synthetic A4/J4-NP, 14-A4-NP (A4-NP), potently suppresses lipopolysaccharideinduced expression of inducible nitric-oxide synthase and cyclooxygenase-2 in macrophages. Furthermore, A4-NP blocks lipopolysaccharide-induced NF-κB activation via inhibition of Iκ kinase-mediated phosphorylation of IκBα. Mutation on Iκ kinase β cysteine 179 markedly diminishes the effect of A4-NP, suggesting that A4-NP acts via thiol modification at this residue. Accordingly, the effects of A4-NP are independent of peroxisome proliferator-activated receptor-γ and are dependent on an intact reactive cyclopentenone ring. Interestingly, free radical-mediated oxidation of DHA greatly enhances its anti-inflammatory potency, an effect that closely parallels the formation of A4/J4-NPs. Furthermore, chemical reduction or conjugation to glutathione, both of which eliminate the bioactivity of A4-NP, also abrogate the anti-inflammatory effects of oxidized DHA. Thus, we have demonstrated that A4/J4-NPs, formed via the oxidation of DHA, are potent inhibitors of NF-κB signaling and may contribute to the anti-inflammatory actions of DHA. These findings have implications for understanding the anti-inflammatory properties of ω-3 fatty acids, and elucidate novel interactions between lipid peroxidation products and inflammation.

Toggling enantioselective catalysis—a promising paradigm in the development of more efficient and versatile enantioselective synthetic methodologies

The increasingly needed synthesis of both enantiomers of a chiral compound usually requires the use of both enantiomers of a chiral catalyst. Several of the usually employed chiral ligands are naturally available in only one enantiomeric form, the antipode often being of labor-intensive preparation. Enantiodivergent asymmetric catalysis has accrued in importance in this regard, in that it allows expeditious access to both enantiomers of a product without any direct modification on the chemical structure of the chiral promoter. Various promising examples will be discussed throughout the review. If available or envisageable, a mechanistic rationale for the observed enantioinversion will be outlined.

Anhydrous lanthanum trichloride, a mild and convenient reagent for thioacetalization

Abstract Carbonyl compounds are thioacetalyzed easily by 1,2-ethanedithiol in the presence of anhydrous LaCl 3 .

Dialdehyde sesquiterpenes and other terpenoids as vanilloids

Selected naturally occurring unsaturated dialdehyde sesquiterpenes and related bioactive terpenoids were assayed for vanilloid-like activity. Out of the 25 compounds tested, eight inhibited completely the specific binding of [3H]resiniferatoxin by rat spinal cord membranes: binding affinities ranged from 0.6 microM for cinnamodial to 19.0 microM for hebelomic acid F. These values were comparable to the binding affinity of capsaicin (2.7 microM). With the exception of four ligands, compounds that inhibited resiniferatoxin binding to rat spinal cord membranes were also pungent on the human tongue where they showed cross-tachyphylaxis with capsaicin. As expected from their reactive nature, these compounds possess additional sites of action, as reflected in the complex behavior of the stimulation of calcium influx by cinnamodial and cinnamosmolide at high concentrations. This observation might explain the unexpectedly weak membrane depolarization by cinnamodial compared to capsaicin. We conclude that a range of sesquiterpene dialdehydes and related terpenoids, both pungent and non-pungent, may function as vanilloids. These compounds may represent a new chemical lead for the development of vanilloid drugs, structurally unrelated to either capsaicin or resiniferatoxin.

Anti-secretory, anti-inflammatory and anti-Helicobacter pylori activities of several fractions isolated from Piper carpunya Ruiz & Pav.

ETHNOPHARMACOLOGICAL RELEVANCE The leaves of Piper carpunya Ruiz & Pav. (syn Piper lenticellosum C.D.C.) (Piperaceae), are widely used in folk medicine in tropical and subtropical countries of South America as an anti-inflammatory, anti-ulcer, anti-diarrheal and anti-parasitical remedy as well as an ailment for skin irritations. AIMS OF THE STUDY To study the anti-inflammatory, anti-secretory and anti-Helicobacter pylori activities of different fractions isolated from an ethanolic extract of the leaves of Piper carpunya, in order to provide evidence for the use of this plant as an anti-ulcer remedy. Moreover, to isolate the main compounds of the extract and relate their biological activity to the experimental results obtained with the fractions. MATERIALS AND METHODS Sixteen fractions were obtained from the ethanolic extract (F I-XVI) and 16 pure compounds were isolated and identified from these fractions. We studied the effects of the fractions (0.1-400microg/mL) on the release of myeloperoxidase (MPO) enzyme from rat peritoneal leukocytes, on rabbit gastric microsomal H(+), K(+)-ATPase activity and anti-Helicobacter pylori anti-microbial activity using the microdilution method (MM). The main compounds contained in the fractions were isolated and identified by (1)H- and (13)C NMR spectra analysis and comparison with the literature data. RESULTS Eight fractions showed inhibition of MPO enzyme (F I-IV, X, XII, XIV and XV). The highest inhibition was observed with F XIV (50microg/mL, 60.9%, p<0.001). F X and XII were the most active ones, inhibiting the gastric H(+), K(+)-ATPase activity with IC(50) values equal to 22.3microg/mL and 28.1microg/mL, respectively. All fractions, except F XV, presented detectable anti-Helicobacter pylori activity, with a diameter of inhibition zones ranging from 11mm up to 50mm. The best anti-Helicobacter pylori activity was obtained with F III and V. Both fractions killed Helicobacter pylori with lowest concentration values, about 6.25mug/mL. Sixteen pure compounds were isolated, five of them are flavonoids that possess strong anti-oxidant and free radical scavenging activity, e.g. vitexin, isovitexin, and rhamnopyranosylvitexin. Terpenoids like sitosterol, stigmasterol and phytol, which have shown gastroprotective activity, and dihydrochalcones, like asebogenin, with anti-bacterial activity, were also isolated. Furthermore, the rare neolignan 1, that is a DNA polymerase beta lyase inhibitor, and (6S, 9S)-roseoside, that shows strong anti-bacterial activity, were isolated, for the first time, from the genus Piper. CONCLUSIONS We suggest that the flavonoids isolated from F I and II (vitexin, isovitexin, rhamnopyranosylvitexin and isoembigenin) contribute to the anti-MPO activity, as well as to their anti-Helicobacter pylori activity. These flavonoids may also be responsible for the important inhibition of H(+), K(+)-ATPase activity. Also the phytosterols and phytol obtained from F XIV and XV could be involved in these gastroprotective activities. These results encourage us to continue phytochemical studies on these fractions in order to obtain full scientific validation for this species.

A Simple and Versatile Re‐Catalyzed Meyer–Schuster Rearrangement of Propargylic Alcohols to α,β‐Unsaturated Carbonyl Compounds

Rhenium does the job! A readily available rhenium complex efficiently catalyzed the direct Meyer-Schuster-like rearrangement of different alkyl- and aryl-substituted propargylic secondary and tertiary alcohols to the corresponding alpha,beta-unsaturated compounds, which were produced with virtually complete E stereoselectivity. The reaction proceeded under neutral conditions and no racemization of potentially enolizable stereocenters was observed.

Coatline A and B, two C-glucosyl-α-hydroxydihydrochalcones from Eysenhardtia polystachya

Abstract The first two examples of naturally occurring C -glucosyl-α-hydroxydihydrochalcones have been isolated from Eysenhardtia polystachya , a Mexica

Tricholomenyns A and B, novel antimitotic acetylenic cyclohexenone derivatives from the fruiting bodies of Tricholoma acerbum

Abstract Tricholomenyns A and B, isolated from the fruiting bodies of Tricholoma acerbum , and identified by analysis of 2D-NMR data and chemical reactions, efficiently arrested mitosis of T lymphocytes cultures.

Neurotoxic lipid peroxidation species formed by ischemic stroke increase injury.

Stroke is the third leading cause of death in the United States, yet no neuroprotective agents for treatment are clinically available. There is a pressing need to understand the signaling molecules that mediate ischemic cell death and identify novel neuroprotective targets. Cyclopentenone isoprostanes (IsoPs), formed after free radical-mediated peroxidation of arachidonic acid, are used as markers of stress, but their bioactivity is poorly understood. We have recently shown that 15-A(2t)-IsoP is a potent neurotoxin in vitro and increases the free radical burden in neurons. In this work, we demonstrate that 15-A(2t)-IsoP is abundantly produced in stroke-infarcted human cortical tissue. Using primary neuronal cultures we found that minimally toxic exposure to 15-A(2t)-IsoP does not alter ATP content, but in combination with oxygen glucose deprivation resulted in a significant hyperpolarization of the mitochondrial membrane and dramatically increased neuronal cell death. In the presence of Ca(2+), 15-A(2t)-IsoP led to a rapid induction of the permeability transition pore and release of cytochrome c. Taken with our previous work, these data support a model in which ischemia causes generation of reactive oxygen species, calcium influx, lipid peroxidation, and 15-A(2t)-IsoP formation. These factors combine to enhance opening of the permeability transition pore leading to cell death subsequent to mitochondrial cytochrome c release. These data are the first documentation of significant 15-A(2t)-IsoP formation after acute ischemic stroke and suggest that the addition of 15-A(2t)-IsoP to in vitro models of ischemia may help to more fully recapitulate stroke injury.

Sesquiterpenes from Lactarius blennius

Abstract Six sesquiterpene lactones were isolated from Lactarius blennius. The structures of two new sesquiterpenes, blennin A and blennin B were determinated by spectroscopic methods and the structure of the seco-compound, blennin C, is revised. The two known furan sesquiterpenes and lactarorufin A were also identified.