Unsaturated Lactones Research Articles

Pleurotus ostreatus as a Biocatalyst to Obtain Bicyclic Hydroxylactones with Three or Four Methyl Groups

The purpose of the study was to explore microbial transformations in cultures of basidiomycetes Pleurotus ostreatus, two bicyclic unsaturated lactones occurring in the form of two diastereoisomers. Some of these strains were able to transform unsaturated lactones into four known and three new derivatives. The structures of all lactones were established on the basis of spectroscopic data. Both substrates and products caused a complete inhibition of growth of A. alternata and F. linii strains.

New Unsaturated Lactones and a Meroterpenoid from Ganoderma lucidum

From the dried fruiting bodies of Ganoderma lucidum, 2 new unsaturated lactones, dayaolingzhilactones A and B (1 and 2), and 1 new meroterpenoid, dayaolingzhiol H (3), together with 10 known compounds (4-13), were isolated. Their chemical structures were identified by using spectroscopic data and calculated specific rotation. The inhibitory activities of compounds 1 and 2 toward acetylcholinesterase (AchE) were assessed in vitro with tacrine as the positive control. Both of them exhibited moderate AchE inhibitory activities at the concentration of 50 μM.

Sesquiterpene fractions of Artemisia plants as potent inhibitors of inducible nitric oxide synthase and cyclooxygenase-2 expression.

Objective(s): Artemisia species are important medicinal plants throughout the world. Some species are traditionally used for their anti-inflammatory effect. The present study was designed to isolate sesquiterpene fractions from several Artemisia species and evaluate their anti-inflammatory activities on key mediators and signaling molecules involved in regulation of inflammation.Materials and Methods:Sesquiterpene fractions were prepared from several Artemisia species using the Herz-Högenauer technique. Lipopolysaccharide (LPS)-stimulated J774A.1 macrophages were exposed to isolated fractions. Their possible cytotoxic effect was examined using MTT assay. In addition, nitric oxide (NO) release was measured using Griess method and prostaglandin E2 (PGE2) level was determined by enzyme-linked immunosorbent assay (ELISA). Moreover, protein expression of pro-inflammatory enzymes, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were investigated using Western blot analysis. Results:Nitric oxide level produced by LPS-primed macrophages was significantly decreased with all prepared fractions in a dose-dependent manner. Saturated sesquiterpene lactones-rich species (Artemisia kopetdaghensis, Artemisia santolina, Artemisia sieberi) showed the highest suppressive activity on NO and PGE2 production via suppression of iNOS and COX-2 expression. Fractions bearing unusual (Artemisia fragrans and Artemisia absinthium) and unsaturated sesquiterpene lactones (Artemisia ciniformis) possess less modulatory effect on PGE2 production and COX-2 expression. Conclusion:It can be concluded that some of the medicinally beneficial effects attributed to Artemisia plants may be associated with the inhibition of pro-inflammatory signaling pathways. However, these effects could be dependent on the type of their sesquiterpene content. These findings also introduce new Artemis species cultivated in Iran as a useful anti-inflammatory agents.

Synthesis of 23-, 25-, 27-, and 29-Membered ( Z)-Selective Unsaturated and Saturated Macrocyclic Lactones from 16- and 17-Membered Macrocyclic Lactones and Bromoalcohols by Wittig Reaction, Yamaguchi Macrolactonization, and Photoinduced Decarboxylative Radical Macrolactonization.

A new strategy for the synthesis of 23-, 25-, 27-, and 29-membered ( Z)-selective unsaturated and saturated macrocyclic lactones from commercially available 16- and 17-membered macrocyclic lactones and bromoalcohols by Wittig reaction, Yamaguchi macrolactonization, and photoinduced decarboxylative radical macrolactonization is described. The position of the unsaturated part in the macrocyclic lactones can be controlled by changing the number of carbons in the starting materials. This protocol can provide facile access to the desired large-ring ( Z)-selective unsaturated and saturated macrocyclic lactones from simple starting materials.

Industrial Riboflavin Fermentation Broths Represent a Diverse Source of Natural Saturated and Unsaturated Lactones.

Fermentation broths of Ashbya gossypii from the industrial production of riboflavin emit an intense floral, fruity, and nutty smell. Typical Ehrlich pathway products, such as 2-phenylethan-1-ol and 2-/3-methylbutan-1-ol, were detected in large amounts as well as some intensely smelling saturated and unsaturated lactones, e.g., γ-decalactone and γ-(Z)-dodec-6-enlactone. An aroma extract dilution analysis identified 2-phenylethan-1-ol and γ-(Z)-dodec-6-enlactone as the main contributors to the overall aroma, with flavor dilution factors of 32 768. The position of the double bonds of unsaturated lactones was determined by the Paternò-Büchi reaction, and reference compounds that were not available commercially were synthesized to elucidate the structures of the uncommon lactones. The absolute configuration and enantiomeric excess values of the lactones were determined by converting the lactones to their corresponding Mosher's esters. In addition, the odor impressions and odor thresholds in air were determined.

Patulin Induced Dominant Lethal Gene in Mature Male and/or Female Rats

Many fungi including Penicillium and Aspergillus species produces patulin in the contaminated foods. Patulin is a heterocyclic unsaturated lactone that reacts with SH group of biological molecules causing harmful effects in human and animal tissues. Hence, the present investigation was designed to evaluate the possible teratogenic effect of patulin (0.002mg/kg b. wt) which was examined through the induction of dominant lethal gene and the alteration in number of live births in the female rats . Results and Conclusion: patulin is a dangerous teratogen in rats. This was confirmed by the significant increase in the percentage of maternal and embryo toxicities.

Toxicity of Milkweed Leaves and Latex: Chromatographic Quantification Versus Biological Activity of Cardenolides in 16 Asclepias Species.

Cardenolides are classically studied steroidal defenses in chemical ecology and plant-herbivore coevolution. Although milkweed plants (Asclepias spp.) produce up to 200 structurally different cardenolides, all compounds seemingly share the same well-characterized mode of action, inhibition of the ubiquitous Na+/K+ ATPase in animal cells. Over their evolutionary radiation, milkweeds show a quantitative decline of cardenolide production and diversity. This reduction is contrary to coevolutionary predictions and could represent a cost-saving strategy, i.e. production of fewer but more toxic cardenolides. Here we test this hypothesis by tandem cardenolide quantification using HPLC (UV absorption of the unsaturated lactone) and a pharmacological assay (in vitro inhibition of a sensitive Na+/K+ ATPase) in a comparative study of 16 species of Asclepias. We contrast cardenolide concentrations in leaf tissue to the subset of cardenolides present in exuding latex. Results from the two quantification methods were strongly correlated, but the enzymatic assay revealed that milkweed cardenolide mixtures often cause stronger inhibition than equal amounts of a non-milkweed reference cardenolide, ouabain. Cardenolide concentrations in latex and leaves were positively correlated across species, yet latex caused 27% stronger enzyme inhibition than equimolar amounts of leaf cardenolides. Using a novel multiple regression approach, we found three highly potent cardenolides (identified as calactin, calotropin, and voruscharin) to be primarily responsible for the increased pharmacological activity of milkweed cardenolide mixtures. However, contrary to an expected trade-off between concentration and toxicity, later-diverging milkweeds had the lowest amounts of these potent cardenolides, perhaps indicating an evolutionary response to milkweed's diverse community of specialist cardenolide-sequestering insect herbivores.

Targeted synthesis of macrodiolides containing bis-methylene-separated Z-double bonds and their antitumor activity in vitro

An original strategy has been developed for the synthesis of valuable unsaturated macrocyclic lactones, macrodiolides, containing a 1Z,5Z-diene moiety in 57–79% yields and >98% stereoselectivity by hafnium triflate Hf(OTf)4-catalyzed intermolecular esterification of aliphatic α,ω-dicarboxylic acids with α,ω-alka-nZ,(n+4)Z-dienediols (1,12-dodeca-4Z,8Z-dienediol, 1,14-tetradeca-5Z,9Z-dienediol, 1,18-octadeca-7Z,11Z-dienediol). The diols were obtained by homo-cyclomagnesiation of tetrahydropyran ethers of oxygenated 1,2-dienes with EtMgBr in the presence of Mg metal and Cp2TiCl2 catalyst (10 mol. %). The resulting macrodiolides exhibit high cytotoxic activity in vitro against Jurkat, K562, U937, Hek293 and HeLa tumor cell lines.

Rhodium(I)-Catalyzed Decarbonylative Aerobic Oxidation of Cyclic α-Diketones: A Regioselective Single Carbon Extrusion Strategy.

A rhodium-catalyzed decarbonylative aerobic oxidation of cyclic α-diketones has been developed for the first time, where the regioselective formations of α-pyrones and isocoumarins have been achieved. The current decarbonylative aerobic oxidation pathway proceeds via the C-C bond cleavage followed by a C-O bond formation, representing a biomimetic oxidation approach to unsaturated six-membered cyclic lactones. The unique ability of rhodium catalysts to induce the decarbonylative aerobic oxidation opens up a new synthetic toolbox that utilizes the "regioselective single carbon" extrusion strategy.

Thermodynamics of α-angelicalactone polymerization

Thermodynamics of sodium butoxide-catalyzed polymerization of α-angelicalactone (a five-member unsaturated lactone) is studied by calorimetric methods. A polymer with Mw = 2,500 g/mol and the ratio...

Studies towards the total synthesis of Phostriecin

A synthetic approach toward the phostriecin, an antitumor natural product is described. The key features of the present synthesis are Wittig reaction, synthesis of homoallylic alcohol using Brown’s protocol (alkoxyallylboration) and RCM for the creation of unsaturated lactone moiety of phostriecin.

Synthesis of 7-(Hydroxy) Coumarin and Its Activity Test As Antibacterial against Staphylococcus aureus and Shigella flexneri

A synthesis of 7-(hydroxy)coumarin and its activity as antibacterial against Staphylococcus aureus and Shigella flexneri has been performed. The synthesis of the coumarin was carried out by reacting ethyl acetate and 2,4-dihydroxybenzaldehyde using piperidine as an alkaline catalyst via Knoevenagel reaction and antibacterial activity test was performed using disc diffusion method. The product of 7- (hydroxy)coumarin was obtained as a bright brown crystalline (m.p. 125 °C) with a rendment of 77%. The FTIR spectrum shows the absorption of -OH groups at 3101,54 cm-1 and unsaturated lactone groups at 2345.44 cm-1 which is a typical group of coumarin's derivatives. Analysis using 1H-NMR spectrometer also showed the proton of the -OH group appearing on chemical shift (δ) 9.932 ppm. The antibacterial activity test showed that the compound of 7- (hydroxy) coumarin has the highest activity at 20% concentration as an antibacterial against bacteria Staphylococcus aureus and Shigella flexneri with inhibit zone was 24.55 and 20.43 mm, respectively. It means the 7-(hydroxy) coumarin compound has a strong inhibiting activity.

Abstract 90: Inimitable Ouabain: The Endogenous Circulating Cardiotonic Steroid that Singularly Stimulates Sodium Potassium Pump Activity at Low Doses

Rationale: Cardiotonic steroids (CTS), such as digoxin, have been used to treat heart failure (HF) for over 200 years. They inhibit the sodium-potassium pump (NKP), and increase cardiac contractility by inhibiting efflux of sodium through the pump (“digitalis hypothesis”). CTS possess three structural components: a saturated/unsaturated lactone ring, steroid core, and sugar moiety, each of which may be involved in NKP inhibition/stimulation. It is now known that inhibition of the NKP in patients with HF increases mortality, and all major beneficial treatments increase its activity. Endogenous circulating CTS such as ouabain are generally thought to inhibit the NKP, despite studies sporadically reporting ouabain-induced pump stimulation. This study aims to identify whether ouabain-induced pump stimulation occurs, and if so, which structural components are involved in causing pump stimulation. Methods & Results: Cardiac myocytes were isolated from male New Zealand White rabbits, placed in a Tyrode’s solution, and whole-cell patch clamped. They were exposed to 0-30nM ouabain, 0-50nM dihydroouabain (ouabain with a saturated lactone ring) or 0-500nM ouabagenin (ouabain lacking a sugar moiety) for 1 min, followed by a potassium-free solution, with the difference in current yielding the NKP current. Compared to the 0.47±0.05 pA/pF Tyrode’s solution control (n=11), 5nM ouabain significantly increased NKP current to 0.69±0.09 pA/pF ( P <0.05, n=6). Exposure to dihydroouabain or ouabagenin did not significantly change NKP current in the studied concentration range. Cell viability assays carried out on the breast cancer cell line MCF7, which have an NKP structure extremely similar to that of cardiomyocytes, showed significantly elevated viability above control values (n=2) following 24h treatment with 0-9nM ouabain; maximum viability was 116±5% at 0.28nM ( P <0.05, n=4). A significant change in viability was not observed for ouabagenin or digoxin in the same concentration range. Conclusion: Low-dose ouabain uniquely stimulates NKP activity. Low-dose dihydroouabain and ouabagenin do not, suggesting that a sugar moiety and unsaturated lactone ring are required for pump stimulation. Ouabain in its unaltered form may be a potential treatment for HF.

A Cascade of Redox Reactions Generates Complexity in the Biosynthesis of the Protein Phosphatase‐2 Inhibitor Rubratoxin A

AbstractRedox modifications are key complexity‐generating steps in the biosynthesis of natural products. The unique structure of rubratoxin A (1), many of which arise through redox modifications, make it a nanomolar inhibitor of protein phosphatase 2A (PP2A). We identified the biosynthetic pathway of 1 and completely mapped the enzymatic sequence of redox reactions starting from the nonadride 5. Six redox enzymes are involved, including four α‐ketoglutarate‐ and iron(II)‐dependent dioxygenases that hydroxylate four sp3 carbons; one flavin‐dependent dehydrogenase that is involved in formation of the unsaturated lactone; and the ferric‐reductase‐like enzyme RbtH, which regioselectively reduces one of the maleic anhydride moieties in rubratoxin B to the γ‐hydroxybutenolide that is critical for PP2A inhibition. RbtH is proposed to perform sequential single‐electron reductions of the maleic anhydride using electrons derived from NADH and transferred through a ferredoxin and ferredoxin reductase pair.

A Cascade of Redox Reactions Generates Complexity in the Biosynthesis of the Protein Phosphatase-2 Inhibitor Rubratoxin A.

Redox modifications are key complexity-generating steps in the biosynthesis of natural products. The unique structure of rubratoxin A (1), many of which arise through redox modifications, make it a nanomolar inhibitor of protein phosphatase 2A (PP2A). We identified the biosynthetic pathway of 1 and completely mapped the enzymatic sequence of redox reactions starting from the nonadride 5. Six redox enzymes are involved, including four α-ketoglutarate- and iron(II)-dependent dioxygenases that hydroxylate four sp3 carbons; one flavin-dependent dehydrogenase that is involved in formation of the unsaturated lactone; and the ferric-reductase-like enzyme RbtH, which regioselectively reduces one of the maleic anhydride moieties in rubratoxin B to the γ-hydroxybutenolide that is critical for PP2A inhibition. RbtH is proposed to perform sequential single-electron reductions of the maleic anhydride using electrons derived from NADH and transferred through a ferredoxin and ferredoxin reductase pair.

Influence of structure of lactones with the methylcyclohexene and dimethylcyclohexene ring on their biotransformation and antimicrobial activity.

The aim of this article is influence of the structure of lactones with the methylcyclohexene and dimethylcyclohexene ring on their biotransformation and antimicrobial activity. This work was based on the general remark that even the smallest change in the structure of a compound can affect its biological properties. The results of the biotransformation of four bicyclic unsaturated lactones with one or two methyl groups in the cyclohexene ring was tested using fifteen fungal strains (Fusarium species, Penicillium species, Absidia species, Cunninghamella japonica, and Pleurotus ostreatus) and five yeast strains (Yarrowia lipolytica, Rhodorula marina, Rhodorula rubra, Candida viswanathii, and Saccharomyces cerevisiae). During these transformations, new epoxylactone and hydroxylactone were obtained. The relationship between the substrate structure and the ability of the microorganisms to transform them were analysed. Only compounds with C-O bond of lactone ring in the equatorial position were transformed by fungus. All presented here lactones were examined also for their antimicrobial activity. It turned out that these compounds exhibited growth inhibition of bacteria and fungi, mainly Bacillus subtilis, Candida albicans, Aspergillus niger, and Penicillium expansum.

Synthesis and Biotransformation of Bicyclic Unsaturated Lactones with Three or Four Methyl Groups.

The aim of this study was to obtain new unsaturated lactones by chemical synthesis and their microbial transformations using fungal strains. Some of these strains were able to transform unsaturated lactones into different hydroxy or epoxy derivatives. Strains of Syncephalastrum racemosum and Absidia cylindrospora gave products with a hydroxy group introduced into a tertiary carbon, while the Penicillium vermiculatum strain hydroxylated primary carbons. The Syncephalastrum racemosum strain hydroxylated both substrates in an allylic position. Using the Absidia cylindrospora and Penicillium vermiculatum strains led to the obtained epoxylactones. The structures of all lactones were established on the basis of spectroscopic data.

The Reactions of Arylmethylidene(ethylidene)furanones with NNucleophiles

Background: Despite the large number of publications in the synthesis of heterocyclic compounds based on unsaturated lactones, there are no systematic and modern data's on 3-arylmethylidene- 3H-furan-2-ones. These compounds are convenient starting materials for the synthesis of azaheterocycles and are of independent interest as biologically active compounds. This review examines the interaction of (3H) furan-2-ones with a variety of N-nucleophiles. Keywords: 3H-furan-2-ones, 3-arylmethyliden-3H-furan-2-ones, mono- and binucleophilic reagents, amines, 3H-pyrrole-2- ones, pyridazinones, 5H-dihydropyrimidine-4-ones.

Biotransformation of Bicyclic Halolactones with a Methyl Group in the Cyclohexane Ring into Hydroxylactones and Their Biological Activity.

The aim of this study was the chemical synthesis of a series of halo- and unsaturated lactones, as well as their microbial transformation products. Finally some of their biological activities were assessed. Three bicyclic halolactones with a methyl group in the cyclohexane ring were obtained from the corresponding γ,δ-unsaturated ester during a two-step synthesis. These lactones were subjected to screening biotransformation using twenty two fungal strains. These strains were tested on their ability to transform halolactones into new hydroxylactones. Among the six strains able to catalyze hydrolytic dehalogenation, only two (Fusarium equiseti, AM22 and Yarrowia lipolytica, AM71) gave a product in a high yield. Moreover, one strain (Penicillium wermiculatum, AM30) introduced the hydroxy group on the cyclohexane ring without removing the halogen atom. The biological activity of five of the obtained lactones was tested. Some of these compounds exhibited growth inhibition against bacteria, yeasts and fungi and deterrent activity against peach-potato aphid.

Synthesis of Ophiocerins A, B and C, Botryolide E, Decarestrictine O, Stagonolide C and 9‐epi‐Stagonolide C Employing Chiral Hexane‐1,2,3,5‐tetraol Derivatives as Building Blocks

An organocatalytic approach to the synthesis of (2R,3S)‐hexane‐1,2,3,5‐tetraol (11) derivatives (in the forms of different stereoisomers and bearing different protecting groups) has been developed. The key chiral intermediates 11 were prepared with complete stereocontrol through the proline‐catalyzed intermolecular aldol reaction between acetone and d‐glyceraldehyde acetonide. The synthetic utility of the intermediates was demonstrated by their transformation into the title hydroxylated pyrans and a variety of unsaturated lactones through standard synthetic protocols.