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PubMed2001

Lactone-derived carbon-centered radicals: formation and reactivity with oxygen.

[reaction: see text] Several lactones were examined to test the reactivity of carbon-centered radicals toward oxygen. Notably, the radical derived from 2-coumaranone (4) is unreactive toward oxygen, while 2-cuomaranone itself shows enhanced reactivity toward hydrogen abstraction by alkoxyl radicals. We propose that five parameters influence diminished reactivity toward oxygen, i.e., (a) benzylic resonance stabilization, (b) unpaired spin delocalization on oxygen, (c) favorable stereoelectronic effects, (d) electron-withdrawing effects, and (e) steric effects.

Journal Article↗
PubMed2002

Highly stereoselective protonation of the enolate of a bicyclic cycloheptatrienyl lactone occurs on the hindered face.

[reaction: see text] The H/D exchange of the lactone-fused cycloheptatriene 1 is over 1000 times faster than that of the epimer 2. Interconversion of 1 and 2 provides an equilibrium mixture of 1:0.7, showing a similar stability of the isomers. Protonation of the common enolate 7 occurs far more readily on the more hindered face. Cycloheptatrienide anion is bent and as stable as a divinylcarbanion.

Journal Article↗
PubMed2002

Novel synthesis of L-ribose from D-mannono-1,4-lactone.

[reaction: see text] D-Mannono-1,4-lactone was efficiently converted into L-ribose in eight steps. A key step of this synthesis is the cyclization of a gamma-hydroxyalkoxamate under Mitsunobu conditions. It is noteworthy that the O-alkylation product was obtained in 94% yield and that none of the N-alkylation product was detected in this cyclization.

4-Butyrolactone↗
PubMed2003

Highly diastereoselective and asymmetric Diels-Alder reactions of masked o-benzoquinones with chiral racemic and homochiral furans. Synthesis of optically active tricyclic gamma-lactones.

[reaction: see text] The first examples of highly diastereoselective and asymmetric Diels-Alder cycloadditions of in situ generated masked o-benzoquinones (MOBs) with chiral racemic and homochiral furans bearing a chiral center in the alpha-position leading to highly functionalized diastereomeric/enantioselective tricyclic heterocycles and chiral tricyclic gamma-lactones are described.

Journal Article↗
PubMed2003

Efficient entry into medium-ring keto-lactones. The ruthenium tetraoxide-promoted oxidative cleavage of beta-hydroxyethers.

[reaction: see text] A new use of ruthenium tetraoxide is reported. The catalytic oxidative cleavage of hexahydro-benzofuran-3a-ols led to nine-membered ring keto-lactones in moderate to good yields and high purity. The reaction is clean and easily performed using catalytic amounts of ruthenium trichloride and an excess of sodium periodate as a cooxidant.

Journal Article↗
PubMed2004

A readily synthesized and highly active epoxide carbonylation catalyst based on a chromium porphyrin framework: expanding the range of available beta-lactones.

[reaction: see text] Catalytic carbonylation of epoxides to beta-lactones was effected by a highly active and selective bimetallic catalyst comprised of a chromium(III) porphyrin cation and a cobalt tetracarbonyl anion. The complex is readily synthesized from commercially available compounds in high yield. Carbonylation of numerous linear epoxides, as well as bicyclic epoxides derived from 8- and 12-membered hydrocarbons, proceeded with high activity, selectivity, and yield.

Journal Article↗
PubMed2005

New silicon-mediated, sequential ring expansions of n-sized 2-cycloalkenones into hydroxyolefinic n + m + p medium-sized lactones: short synthesis of (-)-phoracantholide-J.

[reaction: see text] In only four steps from 2-cyclopentenone and 2-cyclohexenone, sequential three- or four-atom and then one- to three-atom ring enlargements produce nine- to 12-membered hydroxyolefinic lactones on a gram scale. 2-Cyclopentenone undergoes this serial 5 + 3 + 2 process to form 10-membered ring natural (-)-phoracantholide-J in six linear steps and 26% overall yield.

Journal Article↗
PubMed2006

High chelation control of three contiguous stereogenic centers in the Reformatsky reactions of indium enolates with alpha-hydroxy ketones: unexpected stereochemistry of lactone formation.

[reaction: see text] A boat-type of chelated bicyclic transition state involving highly diastereoselective construction of three contiguous stereogenic centers in the Reformatsky reaction of indium enolates with alpha-alkoxy/hydroxy ketones is proposed. alpha-Hydroxy ketones with indium enolates furnished highly diastereoselective lactones, while alpha-alkoxy ketones gave acyclic esters in moderate selectivities. X-ray structure analyses of key products unequivocally revealed the unexpected stereochemistry of products and the reaction pathway.

Journal Article↗
PubMed2000

A new procedure for the preparation of beta-keto-delta-lactones from sugars and their transformation into glycosyl acceptors in disaccharides synthesis

[reaction: see text] Glycals are effective starting materials for the synthesis of enantiopure beta-ketone-delta-lactones. They are easily transformed, through a two-step, one-pot reaction, into the corresponding alpha,alpha'-dioxothiones which in turn can be quantitatively trapped with dienophiles in inverse electron-demand [4 + 2] cycloadditions. The reaction of dioxothione 8b with endo and exo glucals allowed the elaboration of a new protocol to prepare 2-thio- or 2-deoxydisaccharides stereoselectively.

Journal Article↗
PubMed2000

Enantiocontrolled synthesis of trialkyl-substituted stereogenic carbons. A general route to cis-3,5-dialkyl gamma-lactones

[reaction: see text] Lewis acid treatment of tertiary Co2(CO)6-propargylic alcohols having a stereochemically defined benzyloxy group at the gamma-benzyl position yielded after cobalt demetalation sec-dialkyl bishomopropargylic alcohols in good yields. The reaction is highly stereoselective and predictable, providing pure stereoisomers. The use of benzyl-alpha,alpha'-d2 ethers permitted the stereoselective d-labeling of methines and methylenes. Very simple chemical manipulations provided a general methodology to obtain the enantiomers of 3,5-dialkyl-gamma-lactones.

Journal Article↗
PubMed2004

Inactivation of the cytotoxic activity of repin, a sesquiterpene lactone from Centaurea repens.

Prolonged ingestion of Yellow Starthistle (Centaurea solstitialis) and Russian Knapweed (Centaurea repens) by horses has been shown to result in a fatal neurodegenerative disorder called equine nigropallidal encephalomalacia (ENE). Bioassay-guided fractionation of extracts from Centaurea species using the PC12 cell line have led to the identification of one of several putative agents, which may contribute to ENE, namely, the sesquiterpene lactone (SQL) repin (1), previously linked to ENE due to its abundance in C. repens. To characterize the molecular basis of repin-induced neurotoxicity, the present study was designed to identify reactive functional groups that may contribute overall to its toxicity. The reaction of repin (1) with glutathione (GSH) led to the exclusive addition of GSH to the alpha-methylenebutyrolactone affording a GSH conjugate (3b) that lacked toxicity in the PC12 cell assay, while selective reduction of the alpha-methylenebutyrolactone double bond of 1 also resulted in an analogue (2) that was devoid of toxicity relative to the parent compound. Unlike repin, analogue 2 failed to decrease cellular dopamine levels in PC12 cells, further substantiating the requirement of the alpha-methylenebutyrolactone group. Results from this study are suggestive that GSH depletion by the SQL repin may be a primary event in the etiology of ENE, increasing the susceptibility to oxidative damage.

Animals↗
PubMed1990

Mandelate racemase and muconate lactonizing enzyme are mechanistically distinct and structurally homologous.

Mandelate racemase (MR) and muconate lactonizing enzyme (MLE) catalyse separate and mechanistically distinct reactions necessary for the catabolism of aromatic acids by Pseudomonas putida. The X-ray crystal structure of MR, solved at 2.5 A resolution, reveals that the secondary, tertiary and quaternary structures of MR and MLE are remarkably similar; also, MR and MLE are about 26% identical in primary structure. However, MR has no detectable MLE activity and vice versa. Thus, MR and MLE constitute the first example of enzymes that catalyse different reactions, as opposed to mechanistically identical reactions on different substrates, yet possess sufficient structural and sequence identity that they are likely to have evolved from a common ancestor. The discovery that MR and MLE catalyse different reactions but share a common structural framework has broad implications for the natural evolution of enzymes and metabolic pathways, as well as for the rational modification of enzyme activities.

Binding Sites↗
PubMed1989

Enhanced cytostatic activity of the sesquiterpene lactone eupatoriopicrin by glutathione depletion.

Eupatoriopicrin (EUP), a sesquiterpene lactone from Eupatorium cannabinum L., possesses cytostatic activity. This was demonstrated for FIO 26 cells in vitro with the aid of a clonogenic assay and in vivo by tumour growth delay in FIO 26 and Lewis lung tumour-bearing mice. In vitro the IC50 for 1 h exposure to EUP was 1.5 microgram ml-1 (4.1 nmol ml-1). This concentration depleted about 25% of its cellular GSH concentration. Pretreatment of FIO 26 cells with BSO, resulting in greater than 99%. GSH depletion, enhanced the cytotoxic effect of EUP. The dose-enhancement factor at the level of 10% cell survival was 2.3. Growth inhibition of the Lewis lung carcinoma and the FIO 26 fibrosarcoma, solidly growing in C57Bl mice, was found after i.v. injection of 20 or 40 mg kg-1 EUP, at a tumour volume of about 500 microliters. Pretreatment with BSO at a dose of 4 mmol kg-1 i.p., 6 h before EUP administration, resulted in a significantly stronger growth delay of both tumours compared with EUP only. At the time of EUP treatment, cellular GSH in the tumours was reduced by BSO treatment to about 60%. It is concluded that EUP possesses antitumour activity in vivo and that chemosensitisation of EUP may be accomplished by pretreatment with BSO, indicating that endogenous GSH protects against the cytostatic action of EUP.

Animals↗
PubMed2000

Bromoenol lactone enhances the permeabilization of rat submandibular acinar cells by P2X7 agonists.

The permeabilizing effect of P2X(7) agonists was tested in rat submandibular acinar cells using the uptake of ethidium bromide as an index. The uptake of ethidium bromide by acini incubated at 37 degrees C in the presence of 1 mM ATP increased with time and reached after 5 min about 10% of maximal uptake measured in the presence of digitonin. The response to ATP was dose-dependent (half-maximal concentration around 40 microM) and it was decreased when the temperature was lowered to 25 degrees C. Benzoyl-ATP reproduced the response to ATP (half-maximal concentration around 10 microM). UTP or 2-methylthioATP had no effect. The permeabilization in response to ATP was blocked by oxidized ATP and by magnesium and inhibited by Coomassie blue. ATP increased the activity of a calcium-insensitive phospholipase A(2) (iPLA(2)). Bromoenol lactone (BEL) inhibited the iPLA(2) stimulated by ATP but potentiated the uptake of ethidium bromide in response to the purinergic agonist. From these results it is concluded that the activation of P2X(7) receptors permeabilizes rat submandibular acinar cells. The pore-forming activity of the receptor might be negatively regulated by the concomitant activation of the iPLA(2) by the receptor.

Adenosine Triphosphate↗
PubMed2002

The anti-inflammatory sesquiterpene lactone parthenolide suppresses CD95-mediated activation-induced-cell-death in T-cells.

Apoptosis is a morphologically distinct form of cell death involved in many physiological and pathological processes. The death receptor CD95 (APO-1/Fas) and its ligand (L) CD95L are critically involved in activation-induced-cell-death (AICD) of activated T-cells. Here we show that the anti-inflammatory sesquiterpene lactone parthenolide derived from the European traditional herb-medicine feverfew and many Mexican India medicinal plants suppresses expression of the CD95L and CD95 at the mRNA levels, thus, preventing T-cells from AICD. We demonstrate that parthenolide blocks NF-kappaB binding to the two NF-kappa binding sites of the CD95L promoter and suppresses promoter activity upon T-cell activation. Aberrant expression of CD95 and, particularly CD95L is dangerous and may lead to severe diseases. Our study indicates that parthenolide supports T-cell survival by down-regulating the CD95 system, at least in part, and, therefore, may have therapeutic potential as a new anti-apoptotic substance against AICD in T-cells.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Bacterial N-acylhomoserine lactone-induced apoptosis in breast carcinoma cells correlated with down-modulation of STAT3.

Cell growth is promoted by mitogens and survival factors, which activate intracellular signalling pathways to control cell cycle progression and cellular integrity. Proliferation signals are transmitted through Ras and Rho family small G-proteins coupled to mitogen-activated protein kinase (MAPK) cascades, while survival signals are propagated by lipid-dependent kinases such as phosphatidylinositide 3-kinases (PI3Ks) and protein kinase B (Akt/PKB). Recently, signal transducer and activator of transcription (STAT) proteins were identified as positive regulators of proliferation in a variety of cell types. Persistent activation of these pathways is associated with tumour cell growth, whereas their inhibition can halt proliferation and precipitate apoptotic cell death. The human pathogen Pseudomonas aeruginosa uses quorum-sensing signal molecules (QSSMs) to regulate virulence gene expression. QSSMs also suppress host immune responses although the mechanism of suppression is unknown. Here, we demonstrate that the QSSM N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) from P. aeruginosa blocks proliferation and induces apoptosis in human BC cell lines. Analyses of signalling events reveal that OdDHL has little or no effect on MAPK cascades, partially inhibits the Akt/PKB pathway and ablates STAT3 activity. Pharmacological inhibition of each pathway independently indicates that STAT3 activity is critical for BC cell proliferation and survival, while a constitutively active STAT3 confers resistance to OdDHL. These results support the notion of OdDHL as a bioactive molecule in eukaryotic systems and a paradigm for a novel class of antiproliferative compounds.

4-Butyrolactone↗
PubMed2002

Synthesis of gamma-methylene oxacycles and alpha- and beta-alkylidene lactones via silicon-assisted ring opening of cyclopropyl carbinols.

Cyclopropyl carbinols bearing a (tert-butyldiphenylsilyl)methyl substituent undergo silicon-assisted regioselective ring cleavage and the resulting beta-silyl carbocation is intramolecularly trapped with hydroxy and ester functions to generate gamma-methylene oxacycles and alpha- and beta-alkylidene lactones without the cleavage of the silicon function.

Journal Article↗