ABSTRACT
Nicotine has been shown to enhance object recognition memory in the novel object recognition (NOR) test by activating excitatory neurons in the medial prefrontal cortex (mPFC). However, the exact neuronal mechanisms underlying the nicotine-induced activation of mPFC neurons and the resultant memory enhancement remain poorly understood. To address this issue, we performed brain-slice electrophysiology and the NOR test in male C57BL/6J mice. Whole-cell patch-clamp recordings from layer V pyramidal neurons in the mPFC revealed that nicotine augments the summation of evoked excitatory postsynaptic potentials (eEPSPs) and that this effect was suppressed by N-[3,5-Bis(trifluoromethyl)phenyl]-N'-[2,4-dibromo-6-(2H-tetrazol-5-yl)phenyl]urea (NS5806), a voltage-dependent potassium (Kv) 4.3 channel activator. In line with these findings, intra-mPFC infusion of NS5806 suppressed systemically administered nicotine-induced memory enhancement in the NOR test. Additionally, miRNA-mediated knockdown of Kv4.3 channels in mPFC pyramidal neurons enhanced object recognition memory. Furthermore, inhibition of A-type Kv channels by intra-mPFC infusion of 4-aminopyridine was found to enhance object recognition memory, while this effect was abrogated by prior intra-mPFC NS5806 infusion. These results suggest that nicotine augments the summation of eEPSPs via the inhibition of Kv4.3 channels in mPFC layer V pyramidal neurons, resulting in the enhancement of object recognition memory.
Subject(s)
Mice, Inbred C57BL , Nicotine , Prefrontal Cortex , Recognition, Psychology , Animals , Male , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiology , Prefrontal Cortex/metabolism , Nicotine/pharmacology , Mice , Recognition, Psychology/drug effects , Shal Potassium Channels/metabolism , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Memory/drug effects , Excitatory Postsynaptic Potentials/drug effectsABSTRACT
In this study, we explored anti-inflammatory compounds from the brown alga Dictyopteris polypodioides and isolated 7 meroterpenoids. Their anti-inflammatory activities were evaluated using the lipopolysaccharide-stimulated mouse macrophage cell line, RAW264. Yahazunol (1) exhibited similar nitric oxide (NO) production inhibitory activity as zonarol (2), which has previously been shown to be an anti-inflammatory compound. Yahazunol (1), zonarol (2), and isozonarol (3) inhibited not only NO production but also inducible nitric oxide synthase, interleukin-6, and C-C motif chemokine ligand 2 mRNA expression in RAW264 cells. The structure-activity relationships of the 11 compounds, including their synthetic analogs, revealed the significance of the hydroquinone moiety in the anti-inflammatory activity of these sesquiterpenoids in RAW264 cells. Diacetylated zonarol (9) exhibited an activity comparable to that of zonarol as a result of intracellular deacetylation. These results provide new insights into the anti-inflammatory activity of hydroquinone-containing natural products.
Subject(s)
Anti-Inflammatory Agents , Nitric Oxide , Terpenes , Animals , Mice , Structure-Activity Relationship , Nitric Oxide/biosynthesis , Nitric Oxide/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , RAW 264.7 Cells , Terpenes/pharmacology , Terpenes/chemistry , Terpenes/isolation & purification , Phaeophyceae/chemistry , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Interleukin-6/metabolism , Interleukin-6/genetics , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type II/genetics , Gene Expression Regulation/drug effectsABSTRACT
The red algal genus Portieria is a prolific producer of halogenated monoterpenoids. In this study, we isolated and characterised monoterpenoids from the Okinawan red algae Portieria hornemannii. A new polyhalogenated cyclic monoterpenoid, 2(R)-chloro-1,6(S)-dibromo-3(8)(Z)-ochtoden-4(R)-ol (1), along with three known monoterpenoids, (2R,3(8)E,4S,6R)-6-bromo-2-chloro-1,4-oxido-3(8)-ochtodene (2), 1-bromo-2-chloroochtoda-3(8),5-dien-4-one (3), and 2-chloro-1-hydroxyochtoda-3(8),5-dien-4-one (4) were isolated from the methanol extract of three populations of P. hornemannii. These compounds were characterised using a combination of spectroscopic methods and chemical synthesis, and the absolute stereochemistry of compounds 1 and 2 was determined. In addition, all isolated compounds were screened for their anti-biofouling activity against the mussel Mytilus galloprovincialis, and 1 exhibited strong activity. Therefore, halogenated monoterpenoids have the potential to be used as natural anti-biofouling drugs.
Subject(s)
Biofouling , Monoterpenes , Rhodophyta , Animals , Biofouling/prevention & control , Halogenation , Molecular Structure , Monoterpenes/isolation & purification , Monoterpenes/chemistry , Monoterpenes/pharmacology , Rhodophyta/chemistry , Guanethidine/chemistry , Guanethidine/isolation & purification , Guanethidine/pharmacologyABSTRACT
Histrionicotoxin (HTX) alkaloids, which are isolated from Colombian poison dart frogs, are analgesic neurotoxins that modulate nicotinic acetylcholine receptors (nAChRs) as antagonists. Perhydrohistrionicotoxin (pHTX) is the potent synthetic analogue of HTX and possesses a 1-azaspiro[5.5]undecane skeleton common to the HTX family. Here, we show for the first time the divergent nine-step synthesis of pHTX and its three stereoisomers from the known aldehyde through a one-step construction of the 1-azaspiro[5.5]undecane framework from a linear amino ynone substrate. Surprisingly, some pHTX diastereomers exhibited antagonistic activities on the chicken α4ß2-neuronal nAChRs that were more potent than pHTX.
Subject(s)
Amphibian Venoms , Chickens , Receptors, Nicotinic , Animals , AlkanesABSTRACT
Biomimetic epoxide-opening cascade cyclizations of polyepoxides enable the efficient and rapid construction of polyether skeletons. In this study, we discovered a method for switching the cyclization mode from tetrahydrofuran to tetrahydropyran (THP) formation in epoxide-opening cascades of polyepoxides. The THP formation proceeded via an epoxonium-ion intermediate by simple heating in neutral water. Next, by expanding the switching reaction, we successfully established a "ring-size-divergent" synthetic strategy that enabled the synthesis of the five-, six-, and seven-membered ether rings from identical diepoxide cyclization precursors under simple acidic or neutral conditions. The "ring-size-divergent" synthetic strategy was applied to the short divergent synthesis of nerolidol-type sesquiterpenoids and feroniellins, resulting in the revision of the proposed stereochemistry of certain natural products and the determination of all of the absolute configurations. Additionally, the anti-inflammatory activities of the synthetic samples were evaluated.
Subject(s)
Biological Products , Sesquiterpenes , Epoxy Compounds , Sesquiterpenes/pharmacology , Ethers , Cyclization , Biological Products/pharmacologyABSTRACT
Previous studies postulated that chronic administration of varenicline, a partial and full agonist at α4ß2 and α7 nicotinic acetylcholine receptors (nAChRs), respectively, enhances recognition memory. However, whether its acute administration is effective, on which brain region(s) it acts, and in what signaling it is involved, remain unknown. To address these issues, we conducted a novel object recognition test using male C57BL/6J mice, focusing on the medial prefrontal cortex (mPFC), a brain region associated with nicotine-induced enhancement of recognition memory. Systemic administration of varenicline before the training dose-dependently enhanced recognition memory. Intra-mPFC varenicline infusion also enhanced recognition memory, and this enhancement was blocked by intra-mPFC co-infusion of a selective α7, but not α4ß2, nAChR antagonist. Consistent with this, intra-mPFC infusion of a selective α7 nAChR agonist augmented object recognition memory. Furthermore, intra-mPFC co-infusion of U-73122, a phospholipase C (PLC) inhibitor, or 2-aminoethoxydiphenylborane (2-APB), an inositol trisphosphate (IP3) receptor inhibitor, suppressed the varenicline-induced memory enhancement, suggesting that α7 nAChRs may also act as Gq-coupled metabotropic receptors. Additionally, whole-cell recordings from mPFC layer V pyramidal neurons in vitro revealed that varenicline significantly increased the summation of evoked excitatory postsynaptic potentials, and this effect was suppressed by U-73122 or 2-APB. These findings suggest that varenicline might acutely enhance recognition memory via mPFC α7 nAChR stimulation, followed by mPFC neuronal excitation, which is mediated by the activation of PLC and IP3 receptor signaling. Our study provides evidence supporting the potential repositioning of varenicline as a treatment for cognitive impairment.
Subject(s)
Receptors, Nicotinic , alpha7 Nicotinic Acetylcholine Receptor , Mice , Male , Animals , Varenicline/pharmacology , Receptors, Nicotinic/metabolism , Mice, Inbred C57BL , Prefrontal Cortex/metabolismABSTRACT
Two new eremophilane-type sesquiterpenoids, fusumaols A (1) and B (2), were isolated from the stem-leafy liverwort, Bazzania japonica collected in Mori-Machi, Shizuoka, Japan. Their structures were established using extensive spectroscopic (IR, MS, and 2D NMR) data, and the absolute configuration of 1 was determined by the modified Mosher's method. This is the first time eremophilanes have been discovered in the liverwort genus Bazzania. Compounds 1 and 2 were evaluated for their repellent activity against the adult population of the rice weevil Sitophilus zeamais using the modified filter paper impregnation method. Both sesquiterpenoids showed moderate repellent activities.
Subject(s)
Hepatophyta , Sesquiterpenes , Hepatophyta/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Polycyclic Sesquiterpenes , Sesquiterpenes/pharmacology , Sesquiterpenes/chemistryABSTRACT
One new furanocembranoid diterpene, 11-hydroxy-Δ12(13)-pukalide (1), along with six known secondary metabolites, 11-acetoxy-Δ12(13)-pukalide (2), 13α-acetoxypukalide (3), pukalide (4), 3α-methoxyfuranocembranoid (5), Δ9(15)-africanene (6), and methyl (5'E)-5-(2',6'-dimethylocta-5',7'-dienyl)furan-3-carboxylate (7) were isolated from the Okinawan soft coral Sinularia sp. Their chemical structures were elucidated based on spectroscopic analysis (FTIR, NMR, and HRESIMS), and the relative stereochemistry of 1 was determined by NOESY experiments and acetylation, which yielded derivative 2. In addition, compounds 1 and 7 exhibited toxicity in the brine shrimp lethality test.
ABSTRACT
Sequestration of chemical defenses from dietary sources is dependent on the availability of compounds in the environment and the mechanism of sequestration. Previous experiments have shown that sequestration efficiency varies among alkaloids in poison frogs, but little is known about the underlying mechanism. The aim of this study was to quantify the extent to which alkaloid sequestration and modification are dependent on alkaloid availability and/or sequestration mechanism. To do this, we administered different doses of histrionicotoxin (HTX) 235A and decahydroquinoline (DHQ) to captive-bred Adelphobates galactonotus and measured alkaloid quantity in muscle, kidney, liver, and feces. HTX 235A and DHQ were detected in all organs, whereas only DHQ was present in trace amounts in feces. For both liver and skin, the quantity of alkaloid accumulated increased at higher doses for both alkaloids. Accumulation efficiency in the skin increased at higher doses for HTX 235A but remained constant for DHQ. In contrast, the efficiency of HTX 235A accumulation in the liver was inversely related to dose and a similar, albeit statistically nonsignificant, pattern was observed for DHQ. We identified and quantified the N-methylation of DHQ in A. galactonotus, which represents a previously unknown example of alkaloid modification in poison frogs. Our study suggests that variation in alkaloid composition among individuals and species can result from differences in sequestration efficiency related to the type and amount of alkaloids available in the environment.
Subject(s)
Alkaloids , Poisons , Alkaloids/chemistry , Animals , Anura/physiology , Methylation , QuinolinesABSTRACT
The asymmetric total synthesis of toxicodenane A, a sesquiterpenoid expected to be promising for diabetic nephropathy, was achieved. In the synthesis, a samarium iodide (SmI2)-induced Barbier-type cyclization and a regio- and stereoselective allylic oxidation followed by a dehydration cyclization were employed as key steps. Furthermore, the first asymmetric syntheses of both enantiomers were accomplished using the previously mentioned synthetic strategy. Finally, the synthetic compounds significantly inhibited lipotoxicity-mediated inflammatory and fibrotic responses in mouse renal proximal tubular cells.
Subject(s)
Iodides , SamariumABSTRACT
There are marine cytotoxic bromotriterpenoids, named the thyrsiferol family that are structurally characterized by some tetrahydropyran (THP) and tetrahydrofuran (THF) rings. The thyrsiferol family belongs to natural products that are often difficult to determine their stereostructures even by the current, highly advanced spectroscopic methods, especially in acyclic systems including stereogenic tetrasubstituted carbon centers. In such cases, it is effective to predict and synthesize the possible stereostructures. Herein, to elucidate ambiguous stereostructures and unassigned absolute configurations of aplysiol B, laurenmariannol, and saiyacenol A, members of the thyrsiferol family, we carried out their asymmetric chemical syntheses featuring 6-exo and 5-exo oxacyclizations of epoxy alcohol precursors and 6-endo bromoetherification of a bishomoallylic alcohol. In this paper, we report total assignments of their stereostructures through their asymmetric chemical syntheses and also their preliminary cytotoxic activities against some tumor cells. These results could not have been achieved without depending on asymmetric total synthesis.
ABSTRACT
Sequestration of chemical defenses from dietary sources is dependent on the availability of compounds in the environment and the mechanism of sequestration. Previous experiments have shown that sequestration efficiency varies among alkaloids in poison frogs, but little is known about the underlying mechanism. The aim of this study was to quantify the extent to which alkaloid sequestration and modification are dependent on alkaloid availability and/or sequestration mechanism. To do this, we administered different doses of histrionicotoxin (HTX) 235A and decahydroquinoline (DHQ) to captive-bred Adelphobates galactonotus and measured alkaloid quantity in muscle, kidney, liver, and feces. HTX 235A and DHQ were detected in all organs, whereas only DHQ was present in trace amounts in feces. For both liver and skin, the quantity of alkaloid accumulated increased at higher doses for both alkaloids. Accumulation efficiency in the skin increased at higher doses for HTX 235A but remained constant for DHQ. In contrast, the efficiency of HTX 235A accumulation in the liver was inversely related to dose and a similar, albeit statistically nonsignificant, pattern was observed for DHQ. We identified and quantified the N-methylation of DHQ in A. galactonotus, which represents a previously unknown example of alkaloid modification in poison frogs. Our study suggests that variation in alkaloid composition among individuals and species can result from differences in sequestration efficiency related to the type and amount of alkaloids available in the environment.
ABSTRACT
Feroniellin analogs isolated from Feroniella lucida possess a furanocoumarin skeleton connected to monoterpenic five- to seven-membered ethereal rings by an ether linkage and exhibit a broad spectrum of biological activities. In this contribution, we intended to establish a "ring-size-divergent" synthetic strategy for the monoterpenic five- to seven-membered ethereal rings through the chemical sythesis of feroniellins. The short and comprehensive synthesis of feroniellins was achieved in only two steps from easily available bergamottin based on the "ring-size-divergent" strategy. In addition, these syntheses resulted in revision of the proposed structures for feroniellins A and B and the determination of all the absolute configurations of feroniellins; their preliminary anti-inflammatory activities were investigated as well.
Subject(s)
Cyclization , StereoisomerismABSTRACT
Histrionicotoxin (HTX) alkaloids isolated from the poison arrow frogs possess a unique structure characterized by a 1-azaspiro[5.5]undecane skeleton common to the HTX family. The unique molecular architecture of HTXs and the interest as potential target drugs have prompted synthetic chemists to promote the total synthesis so far. However, all of the synthetic strategies to access the 1-azaspiro[5.5]undecane framework of HTXs take a multistep approach from linear starting materials due to stepwise construction of either six-membered carbo- or azacycle. Herein, we report the direct one-step construction of the 1-azaspiro[5.5]undecane skeleton from linear amino ynone substrates bearing an N-methoxycarbonyl group utilizing our mercuric triflate (Hg(OTf)2 )-catalyzed cycloisomerization reaction. The utility of this novel methodology was demonstrated by the total and formal syntheses of HTX-235A and HTX-283A, respectively, from the azaspirocycle.
ABSTRACT
In this contribution, we propose a new synthetic approach to tetrodotoxin (TTX), one of the most famous marine toxins that, after first preparing a functionalized linear substrate, forms a cyclohexane core from the substrate utilizing our mercuric triflate (Hg(OTf)2)-catalyzed cycloisomerization reaction. The concept was applied to the synthesis of 11-nor-6,7,8-trideoxyTTX and 11-nor-4,9-anhydro-6,7,8-trideoxyTTX, which are unnatural TTX analogues, demonstrating the validity of our new approach.
ABSTRACT
Obesity is a risk factor for many diseases, including type 2 diabetes and cardiovascular disease, and is related to the rising morbidity and mortality. Discovery of agents targeting adipogenesis, especially from natural sources, is important for the treatment of obesity. Here, we aimed to identify anti-adipogenic substances in methanol extracts of Physalis peruviana and to investigate their effect, along with underlying mechanisms. Activity-guided fractionation of the extract revealed 4ß-hydroxywithanolide E (HWE) and withanolide E (WE) as the adipogenesis inhibitors. Both compounds suppressed mRNA expression of central adipogenic transcription factors, peroxisome proliferator-activated receptor γ, and CCAAT/enhancer-binding protein α in the early stage of adipocyte differentiation. The inhibitory action of these two withanolides on adipogenesis was largely limited to this stage. The proliferation of preadipocytes was markedly suppressed by treatment with HWE and WE for 24 and 48 h in the differentiation medium, and cell-cycle arrest in the G0/G1 phase was observed. Therefore, our results suggested that withanolides from P. peruviana to be novel anti-adipogenic compounds that modulate mitotic clonal expansion.
Subject(s)
3T3-L1 Cells/metabolism , Clonal Hematopoiesis/drug effects , Physalis/chemistry , Plant Extracts/chemistry , Ribes/chemistry , Withanolides/metabolism , Adipocytes/metabolism , Animals , Cell Differentiation , Humans , Mice , MitosisABSTRACT
Ambient mass spectrometry is useful for analyzing compounds that would be affected by other chemical procedures. Poison frogs are known to sequester alkaloids from their diet, but the sequestration pathway is unknown. Here, we describe methods for whole-body cryosectioning of frogs and use desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to map the orally administered alkaloid histrionicotoxin 235A in a whole-body section of the poison frog Dendrobates tinctorius. Our results show that whole-body cryosectioning coupled with histochemical staining and DESI-MSI is an effective technique to visualize alkaloid distribution and help elucidate the mechanisms involved in alkaloid sequestration in poison frogs.
Subject(s)
Alkaloids/analysis , Amphibian Venoms/analysis , Anura/physiology , Cryoultramicrotomy/methods , Spectrometry, Mass, Electrospray Ionization/methods , Animals , Tissue Distribution , Whole Body Imaging/methodsABSTRACT
Bone loss and bone-related disease are associated with the deregulation of osteoclast function, and therefore agents that affect osteoclastogenesis have attracted attention. The purpose of the present study was to discover modified kavalactone analogs as potential anti-osteoclastogenic agents. We assessed the effect of 26 analogs on osteoclast differentiation in vitro. The most potent compound, (E)-6-(2-fluorostyryl)-4-methoxy-2H-pyran-2-one (22), suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenic differentiation of RAW264 cells with IC50 values of 4.3 µM. A partial structure-activity relationship study revealed the importance of fluorine and its position within the 5,6-dehydrokawain skeleton. The results of a pit formation assay suggested that compound 22 prevents osteoclastic bone resorption by inhibiting osteoclastogenesis. Moreover, compound 22 downregulated mRNA expression levels of RANKL-induced nuclear factor of activated T cells c1 (NFATc1) and osteoclastogenesis-related genes. These results suggest that (E)-6-(2-fluorostyryl)-4-methoxy-2H-pyran-2-one scaffold could lead to the identification of new anti-resorptive agents.
Subject(s)
Lactones/pharmacology , Osteoclasts/drug effects , Pyrones/pharmacology , Styrenes/pharmacology , Animals , Bone Resorption , Cell Differentiation/drug effects , Fluorine , Mice , Osteogenesis/drug effects , RANK Ligand , RAW 264.7 CellsABSTRACT
Biomimetic epoxide-opening cascades of polyepoxides enable the efficient and rapid construction of polyether frameworks. Herein, we show that the epoxide-opening cascade cyclization that affords tetrahydrofuran products in acidic aqueous media produces tetrahydropyran (THP) in neutral water. THP formation proceeded by simply heating polyepoxides in neutral water and followed a different cyclization mode from those observed so far. The novel cascade cyclization in H2 O was applied to the synthesis of a new nerolidol-type sesquiterpenoid, resulting in revision of the proposed structure and determination of the absolute configuration.
ABSTRACT
An investigation of anti-oxidative compounds from the brown alga Dictyopteris undulata has led to the isolation and identification of isozonarol, isozonarone, chromazonarol, zonaroic acid and isozonaroic acid. Their structures were identified by comparison of MS and NMR spectra. Full NMR assignment and absolute configuration of isozonaroic acid are described. Isozonarol showed the most potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity among the compounds isolated.