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Isatin-derived spirocyclic cores are found in several biologically active molecules. Here, we report nucleophilic domino reactions for the synthesis of α-methylene-γ-butyrolactone/lactam containing spirocyclic oxindoles. The Zn-mediated one-step reaction accommodates a range of substrates and can be used to rapidly generate focused libraries of highly substituted spirocyclic compound.

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Neurodegenerative diseases are incurable and debilitating conditions, characterized by progressive loss and degeneration of vulnerable neuronal populations. Currently, there are no effective therapies available for the treatment of most neurodegenerative disorders. A panel of extracts exhibiting interesting chemical profiles among a high number of bacterial strains isolated from East Mediterranean marine sediments and macroorganisms were evaluated for their activity on TrkB-expressing cells. Among them, the actinobacterial strain Streptomyces sp. BI0788, exhibiting neuroprotective activity in vitro, was selected and cultivated in large-scale. The chemical analysis of its organic extract resulted in the isolation of four new butanolides (1, 4-6), along with two previously reported butanolides (2 and 3) and eight previously reported butenolides (7-14). Compounds 2-4 and 7-14 were evaluated for their neuroprotective effects on TrkB-expressing NIH-3T3 cells. Among them, metabolites 3, 4, 7, 10, 11, 13 and 14 exhibited significant protective activity on the aforementioned cells through the activation of TrkB, the high-affinity receptor for the Brain-Derived Neurotrophic Factor (BDNF), which is well known to play a crucial role in neuronal cell survival and maintenance.

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The Monimiaceae, Siparunaceae, and Atherospermataceae, formerly included in the broad ''old'' Monimiaceae family, have long been known for their uses in traditional medicine and have proven to be rich sources of chemically diverse specialized metabolites with numerous potent biological and therapeutical properties. The progress made recently has expanded their phytochemistry and pharmacology albeit to different extents. This review focuses on the non-volatile constituents isolated from the three plant families during the last two decades and their emerging therapeutic potential. Based on the data collected from multiple databases without statistical analysis, approximately 93 components, of which 35 undescribed compounds including γ-lactones, alkaloids, terpenoids, flavonoids, and homogentisic acid derivatives, have been reported. Moreover, diverse biological activities of pure isolated compounds such as anticancer, antioxidant, antiparasitic, antiviral, and antibacterial activities have been evidenced. Besides offering new important perspectives for different diseases' management, the chemical and biological diversities among the isolated compounds, open promising avenues of research and contribute to renewed interest in these families needing further studies. This review provides an updated overview of their potential as sources of leads for drug discovery, while also highlighting ongoing challenges and future research opportunities.

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In the present study, five known γ-lactones (majoranolide B - 1, majorenolide - 2, majorynolide - 3, lincomolide D - 4, and isolinderanolide E - 5), as well as a new one (perseanolide - 6), were isolated from Persea fulva and P. americana. All isolated compounds exhibited potential activity against trypomastigote forms of Trypanosoma cruzi, whereas compounds 2 (EC50 of 4.8 µM) and 6 (EC50 of 3.6 µM) displayed superior activity than the positive control benznidazole (EC50 of 16.4 µM), with selectivity index (SI) values of 17.8 and >55.6, respectively (benznidazole, SI>12.2). Molecular docking studies were performed for 1-6 against six T. cruzi molecular targets. Using this approach, we observed that, even though perseanolide (6) showed favorable docking to several studied targets, the results were especially promising for hypoxanthine phosphoribosyl transferase (PDB 1TC1). As PDB 1TC1 is associated to the transference of a monophosphorylated ribose from phosphoribosylpyrophosphate (PRPP) in the ribonucleotide synthesis pathway, this interaction may affect the survival of T. cruzi in mammalian cells. The data herein also indicate that possible intermolecular interactions between 6 and PDB 1TC1 derive from (i) hydrogen bonds in the α,ß-unsaturated-γ-lactone unity and (ii) hydrophobic interactions in the long-chain alkyl group. Based on our results, perseanolide (6), reported for the first time in this work, can auspiciously contribute to future works regarding new trypanocidal agents.

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In the total stereo-controlled synthesis of natural prostaglandins (PGs) and their structural analogs, a vast class of compounds and drugs, known as the lactones, are encountered in a few key steps to build the final molecule, as: δ-lactones, γ-lactones, and 1,9-, 1,11-, and 1,15-macrolactones. After the synthesis of 1,9-PGF2α and 1,15-PGF2α lactones, many 1,15-lactones of E2, E3, F2, F3, A2, and A3 were found in the marine mollusc Tethys fimbria and the quest for understanding their biological role stimulated the research on their synthesis. Then 1,9-, 1,11-, and 1,15-PG lactones of the drugs were synthesized as an alternative to the corresponding esters, and the first part of the paper describes the methods used for their synthesis. The efficient Corey procedure for the synthesis of prostaglandins uses the key δ-lactone and γ-lactone intermediates with three or four stereocenters on the cyclopentane fragment to link the PG side chains. The paper describes the most used procedures for the synthesis of the milestone δ-Corey-lactones and γ-Corey-lactones, their improvements, and some new promising methods, such as interesting, new stereo-controlled and catalyzed enantioselective reactions, and methods based on the chemical/enzymatic resolution of the compounds in different steps of the sequences. The many uses of δ-lactones not only for the synthesis of γ-lactones, but also for obtaining 9ß-halogen-PGs and halogen-substituted cyclopentane intermediates, as synthons for new 9ß-PG analogs and future applications, are also discussed.

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This work presents the study of the roots of the Macaronesian paleoendemism Persea indica (L.) Spreng. The root biomass of this protected tree species has been produced by soil-less aeroponic culture under controlled environment. This system has important advantages over traditional plant production techniques because it provides opportunities to optimize the yield of metabolite production under well-controlled conditions, thereby facilitating commercial-scale production of bioactive compounds. Thus, for the first time a study of this type has permitted the isolation from the roots of seven undescribed dextrorotatory lactones: the alkane-γ-lactones (+)-majoranolide and (+)-dihydromajorenolide, the alkene-γ-lactones (+)-majorenolide and (+)-majorenolide acetate, and the alkyne-γ-lactones, (+)-majorynolide, (+)-majorynolide acetate and (+)-isomajorynolide. In addition, thirteen known compounds were also isolated including two possible avocadofurane precursors, avocadynone acetate and avocadenone acetate, the monoterpene esters cis- and trans-p-coumarate of (-)-borneol, and the ryanoid diterpenes cinnzeylanone, anhidrocinnzeylanine, cinnzeylanine, cinnzeylanol, epiryanodol, perseanol, cinncassiol E, perseaindicol and secoperseanol. The configuration at C-14 de two ryanodane diterpenes has also been revised in this work. Furthermore, (-)-borneol cis-p-coumarate has showed to be insecticidal to S. littoralis and cytotoxic to insect (Sf9) cells, (+)-majorenolide antifeedant to aphids and cytotoxic to Sf9, cinnceylanol antifeedant and insecticidal to S. littoralis, and (+)-majorynolide (2), insecticidal against S. littoralis, cytotoxic to Sf9 and nematicidal, suggesting a defensive role for these compounds.

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3-Hydroxy fatty acids have attracted the interest of researchers, since some of them may interact with free fatty acid receptors more effectively than their non-hydroxylated counterparts and their determination in plasma provides diagnostic information regarding mitochondrial deficiency. We present here the development of a convenient and general methodology for the asymmetric synthesis of 3-hydroxy fatty acids. The enantioselective organocatalytic synthesis of terminal epoxides, starting from long chain aldehydes, is the key-step of our methodology, followed by ring opening with vinylmagnesium bromide. Ozonolysis and subsequent oxidation leads to the target products. MacMillan's third generation imidazolidinone organocatalyst has been employed for the epoxide formation, ensuring products in high enantiomeric purity. Furthermore, a route for the incorporation of deuterium on the carbon atom carrying the hydroxy group was developed allowing the synthesis of deuterated derivatives, which may be useful in biological studies and in mass spectrometry studies. In addition, the synthesis of fatty γ-lactones, corresponding to 4-hydroxy fatty acids, was also explored.

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BACKGROUND: Lactones are highly valuable cyclic esters of hydroxy fatty acids that find application as pure fragrances or as building blocks of speciality chemicals. While chemical synthesis often leads to undesired racemic mixtures, microbial production allows obtaining optically pure lactones. The production of a specific lactone by biotransformation depends on the supply of the corresponding hydroxy fatty acid, which has economic and industrial value similar to γ-lactones. Hence, the identification and exploration of microorganisms with the rare natural ability for de novo biosynthesis of lactones will contribute to the long-term sustainability of microbial production. In this study, the innate ability of Ashbya gossypii for de novo production of γ-lactones from glucose was evaluated and improved. RESULTS: Characterization of the volatile organic compounds produced by nine strains of this industrial filamentous fungus in glucose-based medium revealed the noteworthy presence of seven chemically different γ-lactones. To decipher and understand the de novo biosynthesis of γ-lactones from glucose, we developed metabolic engineering strategies focused on the fatty acid biosynthesis and the ß-oxidation pathways. Overexpression of AgDES589, encoding a desaturase for the conversion of oleic acid (C18:1) into linoleic acid (C18:2), and deletion of AgELO624, which encodes an elongase that catalyses the formation of C20:0 and C22:0 fatty acids, greatly increased the production of γ-lactones (up to 6.4-fold; (7.6 ± 0.8) × 103 µg/gCell Dry Weight). Further substitution of AgPOX1, encoding the exclusive acyl-CoA oxidase in A. gossypii, by a codon-optimized POX2 gene from Yarrowia lipolytica, which encodes a specific long chain acyl-CoA oxidase, fine-tuned the biosynthesis of γ-decalactone to a relative production of more than 99%. CONCLUSIONS: This study demonstrates the potential of A. gossypii as a model and future platform for de novo biosynthesis of γ-lactones. By means of metabolic engineering, key enzymatic steps involved in their production were elucidated. Moreover, the combinatorial metabolic engineering strategies developed resulted in improved de novo biosynthesis of γ-decalactone. In sum, these proof-of-concept data revealed yet unknown metabolic and genetic determinants important for the future exploration of the de novo production of γ-lactones as an alternative to biotransformation processes.

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Phthalides and their precursors have demonstrated a large variety of biological activities. Eighteen phthalides were synthesized and tested on the stored grain pest Rhyzopertha dominica. In the screening bioassay, compounds rac-(2R,2aS,4R,4aS,6aR,6bS,7R)-7-bromohexahydro-2,4-methano-1,6-dioxacyclopenta[cd]pentalen-5(2H)-one (15) and rac-(3R,3aR,4R,7S,7aS)-3-(propan-2-yloxy)hexahydro-4,7-methano-2-benzofuran-1(3H)-one (17) showed mortality similar to the commercial insecticide, Bifenthrin® (≥90 %). The time (LT50 ) and dose (LD50 ) necessary to kill 50 % of the R. dominica population were determined for the most efficacious phthalides 15 and 17. Compound 15 presented the lowest LD50 (1.97 µg g-1 ), being four times more toxic than Bifenthrin® (LD50 =9.11 µg g-1 ). Both compounds presented an LT50 value equal to 24 h. When applied at a sublethal dose, both phthalides (especially compound 15), reduced the emergence of the first progeny of R. dominica. These findings highlight the potential of phthalides 15 and 17 as precursors for the development of insecticides for R. dominica control.

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Isobenzofuranones are known for their wide range of biological activities such as fungicide, insecticide, and anticancer. The search for novel bioactive compounds was performed by reaction of epoxide 2 with methanol, ethanol, propan-1-ol, propan-2-ol, and butan-1-ol. The mechanism for the stereoselective and stereospecific epoxide opening with methanol was reasoned by calculating the transition states for the two putative structures (rac)-3a and (rac)-3b. The compound (rac)-3a is the kinetic product as inferred from the lower energies of its transition state (TS1). The 1 H and 13 C nuclear magnetic resonance (NMR) chemical shifts for these two candidate structures were calculated and compared with the experimental data using mean absolute error (MAE) and DP4 analyses. Therefore, the relative stereochemistry of (rac)-3a was established by the mechanism, MAE, and DP4 approaches. The hydroxyl group was acetylated to surpass the problem of signal overlapping of H5 and H6 in the 1 H NMR. The relative stereochemistry of the corresponding ester determined by NMR interpretation was in agreement with the structure of (rac)-3a.

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Volatile compounds, including γ-lactones, in brown and white rice fermented by Lactobacillus paracasei, were compared using gas chromatography-mass spectrometry (GC-MS) with stir-bar sorptive extraction (SBSE). The contents of most esters, alcohols, lactones and some aldehydes were higher in brown rice samples containing higher amount of free fatty acids after fermentation. In particular, the contents of γ-lactones increased more in fermented brown rice containing high amounts of fatty acids than in fermented white rice, suggesting that γ-decalactone and γ-nonalactone were formed from oleic acid and linoleic acid during rice fermentation. In addition, the contents of γ-decalactone in fermented brown rice samples with added 4-hydroxydecanoic acid and ricinoleic acid were determined. The content of γ-decalactone in fermented brown rice samples with added 4-hydroxydecanoic acid was considerably higher than that in the control after fermentation, indicating that 4-hydroxydecanoic acid could be an effective intermediate for the formation of γ-decalactone in rice during fermentation.

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Lactones are well-known aroma compounds in, e.g., fruits and fermented foods as well as in dairy products, such as cream or milk powders. The latter are often used in confectionary products, e.g., milk chocolate. Lactones are suggested to contribute to the distinct aroma of dairy products and have also been reported in milk chocolate. However, data on their contribution to the overall aroma of this type of chocolate are scarce. As a result of their pH-dependent instability and their low volatility, a reliable quantitation of lactones is a challenge. Thus, to allow for a quantitation of nine lactones in one single comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry in electron ionization mode run, new synthetic routes were developed for five carbon-13-labeled γ-lactones and four deuterium-labeled δ-lactones, with the isotope label in the ring to be used in stable isotope dilution assays. The concentrations of the nine lactones were then analyzed in raw and pasteurized cream as well as in a heat-treated raw cream. δ-Dodecalactone and δ-decalactone showed the highest concentrations in both the raw and pasteurized cream. In the latter, δ-dodecalactone reached a 2.5-fold higher concentration compared to the raw cream. Subsequent heat treatments in a lab scale showed a further increase by factors of 13 and 19, respectively, suggesting a high potential of lactone precursors in cream. The results serve as a basis for further studies on lactone formation in other thermally processed products, such as milk chocolate.

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The clerodane diterpenoids 16-oxo-cleroda-3, 13(14) E-diene-15 oic acid (1) and kolavenic acid (2) isolated from Polyalthia longifolia var. pendula (Linn.) were previously reported for their antimicrobial activity. Thus present study was designed to investigate the biofilm inhibiting potential of these diterpenoids (1-2) and five new lactone derivatives (3-7) of 1 against methicillin resistant Staphylococcus aureus (MRSA), Streptococcus mutans, Klebsiella pneumoniae and Proteus mirabilis. Compounds 1 and 3 at 10-20 µg/mL were found to be bacteriostatic and significantly reduced the biofilm formation and metabolically active cells of MRSA and S. mutans up to 90%. Parental diterpenoid (1) at 10 and 16 µg/mL significantly eradicated the preformed biofilm of both pathogens. Both the compounds also delayed acid production at minimum inhibitory (MIC) and sub-inhibitory concentrations (sub MIC). Florescence and scanning electron microscopy further confirms the biofilm inhibiting potential of compounds 1 and 3 and displayed disrupted biofilms at MIC and sub MIC levels. The gene expression of MRSA and S. mutans responsible for biofilm formation was also altered. Moreover, the observed anti-virulence properties and delayed bacterial growth after 10 min of exposure to the test compounds 1 and 3 make them a promising class of antibiofilm agents.

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Four stereoisomers of δ-iodo-γ-lactones with p-isopropylphenyl substituent at ß-position: cis-(4R,5R,6S)-1, cis-(4S,5S,6R)-2, trans-(4R,5S,6R)-3, trans-(4S,5R,6S)-4 with proved antiproliferative activity were subjected to in vitro tests for a better understanding of their anticancer activity. The subject of our interest was a possible relationship between a configuration of chiral centers of the studied lactones and their anticancer potency against a panel of canine cell lines representing hematopoietic (CLBL-1, GL-1, CL-1, CLB70) and mammary gland cancers (P114, CMT-U27, CMT-U309). To determine the anticancer activity of the tested compounds, cell viability and cell metabolic activity were checked using propidium iodide staining and the MTT test. To determine whether the studied compounds cause necrotic or apoptotic cell death, two assays for apoptosis evaluation were performed, annexin V staining and detection of caspase 3/7 activation. Simultaneously, the effects of the compounds on the cell cycle were also examined. The conducted research confirmed the anticancer potential of the tested lactones against canine cancers. The investigated isomers exerted higher activity against canine lymphoma/leukemia cell lines than against mammary tumors, whereas the configuration of stereogenic centers of the examined compounds affected their activity. It has been shown that stereoisomers with 4S configuration (2,4) were more active, and the most potent one was the cis-(4S,5S,6R)-2 isomer. The investigated lactones seemed to initiate the process of apoptosis rather than acting as typical cytostatic agents, as cell death via apoptosis, and no increase in G2-M population in the cell cycle analysis were observed. The presented study demonstrated that all four stereoisomers of δ-iodo-γ-lactones with p-isopropylphenyl substituent at ß-position induced apoptosis via a mitochondrial-mediated, caspase-dependent pathway.

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The enantiomer ratios of chiral volatile organic compounds in fruit distillates were determined by multidimensional gas chromatography using solid-phase microextraction (SPME) as a sample treatment procedure. Linalool and its oxides, limonene, α-terpineol, and nerolidol, were present at the highest concentration levels, while significantly lower amounts of ß-citronellol and lactones were found in the studied samples. However, almost all terpenoids mainly occur as a racemic or near-racemic mixture; enantiomer distribution of some chiral organic compounds in fruit distillates correlated to a botanical origin. In particular, a significant enantiomeric excess of (R)-linalool and (S)-α-terpineol was found only for pear brandy, and likewise the dominance (R)-limonene and the second eluted enantiomer of nerolidol for Sorbus domestica and strawberry, respectively. The distribution of γ-lactones stereoisomers was more nonspecific, with a general excess of the R-enantiomer.

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Phthalides are frequently found in naturally occurring substances and exhibit a broad spectrum of biological activities. In the search for compounds with insecticidal activity, phthalides have been used as versatile building blocks for the syntheses of novel potential agrochemicals. In our work, the Diels-Alder reaction between furan-2(5H)-one and cyclopentadiene was used successfully to obtain (3aR,4S,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aS,4R,7S,7aR)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (2) and (3aS,4S,7R,7aR)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aR,4R,7S,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (3). The endo adduct (2) was brominated to afford (3aR,4R,5R,7R,7aS,8R)-5,8-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aS,4S,5S,7S,7aR,8S)-5,8-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one (4) and (3aS,4R,5R,6S,7S,7aR)-5,6-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aR,4S,5S,6R,7R,7aS)-5,6-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one (5). Following the initial analysis of the NMR spectra and the proposed two novel unforeseen products, we have decided to fully analyze the classical and non-classical assay structures with the aid of computational calculations. Computation to predict the (13) C and (1) H chemical shifts for mean absolute error analyses have been carried out by gauge-including atomic orbital method at M06-2X/6-31+G(d,p) and B3LYP/6-311+G(2d,p) levels of theory for all viable conformers. Characterization of the novel unforeseen compounds (4) and (5) were not possible by employing only the experimental NMR data; however, a more conclusive structural identification was performed by comparing the experimental and theoretical (1) H and (13) C chemical shifts by mean absolute error and DP4 probability analyses. Copyright © 2016 John Wiley & Sons, Ltd.

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Natural phytotoxins and their synthetic analogs are a potential source of new bioactive compounds for agriculture. Analogs of rubrolides, a class of γ-alkylidene-γ-lactones isolated from different ascidians, have been shown to interfere with the photosynthetic electron-transport chain, yet their activity needs to be improved. With this aim, ten 5-aryl-6-benzyl-4-bromopyridazin-3(2H)-ones were prepared in yields ranging from 44 to 88% by reaction of their correspondent γ-alkylidene-γ-lactones with NH2 NH2 . The structures of these rubrolide analogs were determined by (1) H- and (13) C-NMR, 2D-NMR (COSY and HETCOR), NOE difference, and MS techniques. These compounds were evaluated for their abilities of interfering with the light-driven reduction of ferricyanide by isolated spinach chloroplasts. Lactones with electron-withdrawing substituents in the para-position of the benzylidene ring were the most effective inhibitors. Characterization of the activity of 11b/11b' suggested a mechanism based on the interaction with the plastoquinone binding site of photosystem II. Addition of several compounds to the culture medium of a cyanobacterial model strain was found to inhibit algal growth. However, the relative effectiveness was not consistent with their activity in vitro, suggesting the occurrence of multiple targets and/or detoxyfication mechanisms. Indeed, the compounds showed differential effects on the heterotrophic growth of some crop species, Cucumis sativus and Sorghum bicolor. Pyridazin-3(2H)-ones 12e, 12i, and 12j, which have been found poorly active against the photosynthetic electron transport, were the most effective in inhibiting the growth of some weeds, Ipomoea grandifolia and Brachiaria decumbens, under greenhouse conditions.

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Herein, the first example of chloropalladation-initiated asymmetric intermolecular carboesterification of alkenes with alkynes by using chiral amine auxiliaries is reported. The use of (1S,2S)-N(1),N(1)-dimethylcyclohexane-1,2-diamine auxiliaries is essential for providing α-methylene-γ-lactones products in moderate to high yields and excellent enantioselectivities at room temperature. Moreover, the chiral amine auxiliaries can be readily removed by hydrolysis during the reaction process to keep the absolute configuration. This oxygen- and water-promoted asymmetric reaction opens a new window to study asymmetric processes in halopalladation reactions.

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PPARγ and Nrf2 are important transcriptional factors involved in many signaling pathways, especially in the anti-infectious response of macrophages. Compounds bearing a Michael acceptor moiety are well known to activate such transcriptional factors, we thus evaluated the potency of α,ß-unsaturated lactones synthesized using fluorous phase organic synthesis. Compounds were first screened for their cytotoxicity in order to select lactones for PPARγ and Nrf2 activation evaluation. Among them, two α-methylene-γ-lactones were identified as potent dual activators of PPARγ and Nrf2 in macrophages.

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Seven ß-aryl substituted γ-alkylidene-γ-lactones analogues of rubrolides were synthesized from mucobromic acid and converted through a lactamization with isobutylamine into their corresponding γ-hydroxy-γ-lactams (76-85%). These lactams were converted into (Z)- and (E)-γ-alkylidene-γ-lactams (23-45%). All compounds were fully characterized by IR, NMR ((1)H and (13)C), COSY and HETCOR bidimensional experiments, and NOE difference spectroscopy experiments when necessary. Evaluation of these three different classes of compounds against Enterococcus faecalis biofilm formation showed that all classes are active and the highest biofilm inhibition activity was caused by lactam 13f (IC50 = 0.76 µg/mL). Moreover, in almost all cases at least one of the lactams is more active than its correspondent γ-alkylidene-γ-lactone. The use of rubrolides as a lead structure has proven successful for the identification of new compounds displaying novel antibacterial activities, namely biofilm inhibition, which have the potential for the development of antimicrobial drugs targeted to inhibition of the initial stages of bacterial infections, rather than bacterial viability. Such drugs are less prompt to induce bacterial resistance, being therefore a more cost-effective investment for pharmaceutical research.

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