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Alkaloid-based urea derivatives were produced with high yield through the reaction of anabasine and cytisine with isoxazolylphenylcarbamates in boiling benzene. Their antitumor activity, in combination with the commonly used five anticancer drugs, namely cyclophosphane, fluorouracil, etoposide, cisplatin, ribomustine with different mechanisms of action, was investigated. Based on the quantum chemical calculations data and molecular docking, hypotheses have been put forward to explain their mutual influence when affecting C6 rat glioma model cells. [ABSTRACT FROM AUTHOR]

Alkaloid-based urea derivatives were produced with high yield through the reaction of anabasine and cytisine with isoxazolylphenylcarbamates in boiling benzene. Their antitumor activity, in combination with the commonly used five anticancer drugs, namely cyclophosphane, fluorouracil, etoposide, cisplatin, ribomustine with different mechanisms of action, was investigated. Based on the quantum chemical calculations data and molecular docking, hypotheses have been put forward to explain their mutual influence when affecting C6 rat glioma model cells.

Aminophthalide derivatives of cytisine, anabasine, and salsoline were obtained in high yields via condensation of the alkaloids with o-formylbenzoic acid. Their structures were proven using 1H and 13C NMR spectroscopy and data from 2D COSY 1H–1H and HMQC 1H–13C spectra. Studies of their antimicrobial activity showed moderate antimicrobial activity of 3-(N-cytisin-1-yl)isobenzofuran-1(3H)-one and 3-(N-salsolin-1-yl)isobenzofuran-1(3H)-one against Gram-positive test strain Staphylococcus aureus ATCC 6538 and Gram-negative test strain Escherichia coli ATCC 25922. [ABSTRACT FROM AUTHOR]

Cleft lip and palate is one of the most common craniofacial anomaly. The management of this entity has led to the development of the field of craniofacial surgery. Improvement in understanding of clefts and refinement in surgical techniques have improved the life of children with clefts. However, like with all congenital anomalies, the impulse is to look earlier. Fetal management of cleft lip and palate is an attractive avenue. In this paper we explore this less travelled road, to see the advances in the field of detection of cleft lip and palate in the fetus, and to see the current state of fetal surgery for cleft lip and palate.

Ulcerative colitis (UC) is an intractable disease that causes persistent colonic inflammation. Numerous studies have reported that smoking can afford clinical benefits in UC. This study aimed to elucidate whether nicotine, the main component in cigarettes, can exert pharmacological effects against experimental UC. To achieve this objective, we compared the effects of nicotine with those of structural nicotine analogs in a UC rodent model (Slc: Wistar rats, male, 9-week-old, and 220–250 g/rat). Nicotine, or a respective structural analog (nornicotine, cotinine, anabasine, myosmine, and anatabine), was administered intraperitoneally daily to rats (n = 6/group) exhibiting dextran sulfate sodium-induced experimental colitis. Examining the colon tissues of model rats, we compared disease severity, cytokine secretion, and α7 nicotine acetylcholine receptor (nAChR7) expression. We observed that nicotine administration induced weight loss at 2.35% in 10 days. Notably, the reduction in histological severity (score) of UC was more pronounced in rats treated with nicotine (score = 4.83, p = 0.042) than in untreated rats (score = 8.17). Nicotine administration increased nAChR7 expression 6.88-fold (p = 0.022) in inflammatory sites of the colon, mainly by suppressing the production of interleukin (IL)-1β and IL-6. Moreover, the secretion of these cytokines was suppressed in lipopolysaccharide-stimulated rat macrophages (MΦ) treated with nicotine. In conclusion, nicotine better alleviates experimental UC than the examined structural analogs by activating nAChR7 expression and suppressing proinflammatory cytokines in MΦ. [ABSTRACT FROM AUTHOR]

Nemerteans (also called Nemertines) are a phylum of predominantly marine worms that use toxins to capture prey and to defend themselves against predators. Hoplonemerteans have a proboscis armed with one or more stylets used in prey capture and are taxonomically divided into Order Monostilifera, whose members possess a single large proboscis stylet, and Order Polystilifera, whose members have multiple small stylets. Many monostiliferans contain alkaloidal toxins, including anabaseine, that stimulate and then desensitize nicotinic acetylcholine receptors that are present in all animals. These compounds also interact with pyridyl chemoreceptors in crustaceans, reducing predation and larval settlement. Anabaseine has been a lead compound in the design of alpha7 nicotinic acetylcholine receptor agonists like GTS-21 (also called DMXBA) to treat disorders of cognition such as Alzheimer's disease and schizophrenia. These drug candidates also display anti-inflammatory activities of potential medical importance. Most polystiliferans live deep in open oceans and are relatively inaccessible. We fortunately obtained two live specimens of a large benthic polystiliferan, Paradrepanophorus crassus (Pc), from the coast of Spain. MS and NMR analyses of the Ehrlich's reagent derivative allowed identification of anabaseine. A spectrophotometric assay for anabaseine, also based on its reaction with Ehrlich's reagent, revealed high concentrations of anabaseine in the body and proboscis. Apparently, the biosynthetic mechanism for producing anabaseine was acquired early in the evolution of the Hoplonemertea, before the monostiliferan-polystiliferan divergence. [ABSTRACT FROM AUTHOR]

Cleft lip and palate is one of the most common craniofacial anomaly. The management of this entity has led to the development of the field of craniofacial surgery. Improvement in understanding of clefts and refinement in surgical techniques have improved the life of children with clefts. However, like with all congenital anomalies, the impulse is to look earlier. Fetal management of cleft lip and palate is an attractive avenue. In this paper we explore this less travelled road, to see the advances in the field of detection of cleft lip and palate in the fetus, and to see the current state of fetal surgery for cleft lip and palate. [ABSTRACT FROM AUTHOR]

The alkaloid-rich fraction obtained by fractionation of the crude methanolic extract of the leaves of wild tobacco tree Nicotiana glauca Graham (Solanaceae) was analyzed using UPLC-MS and GC-MS. Anabasine, a piperidine alkaloid, was identified as the major constituent with approximately 60 % (m/m) of the alkaloid-rich fraction. In addition to anabasine, six secondary metabolites were identified using high-resolution UPLC-MS. Anabasine was quantified in the leaves to be 1 mg g−1 dry plant material. The GC-MS analysis revealed five compounds with anabasine as the major component, while nicotine was not detected. Moreover, GC-MS was used for the analysis of the volatile oil that was obtained by hydro-distillation from the leaves of N. glauca. The volatile plant oil was found to be rich in oxygenated sesquiterpenes (e.g., β-bisabolol) and carboxylic acids and esters (e.g., ethyl linoleate and hexadecanoic acid), whereas anabasine was not detected.

Increasing use of non-combusted forms of nicotine such as e-cigarettes poses important public health questions regarding their specific risks relative to combusted tobacco products such as cigarettes. To fully delineate these risks, improved biomarkers that can distinguish between these forms of nicotine use are needed. Prior work has suggested that methylation status at cg05575921 may serve as a specific biomarker of combusted tobacco smoke exposure. We hypothesized combining this epigenetic biomarker with conventional metabolite assays could classify the type of nicotine product consumption. Therefore, we determined DNA methylation and serum cotinine values in samples from 112 smokers, 35 e-cigarette users, 19 smokeless tobacco users, and 269 controls, and performed mass spectroscopy analyses of urine samples from all nicotine users and 22 verified controls to determine urinary levels of putatively nicotine product-specific substances; propylene glycol, 2-cyanoethylmercapturic acid (CEMA), and anabasine. 1) Cigarette smoking was associated with a dose dependent demethylation of cg05575921 and increased urinary CEMA and anabasine levels, 2) e-cigarette use did not demethylate cg05575921, 3) smokeless tobacco use also did not demethylate cg05575921 but was positively associated with anabasine levels 4) CEMA and cg05575921 levels were highly correlated and 5) propylene glycol levels did not reliably distinguish use groups. Cg05575921 assessments distinguish exposure to tobacco smoke from smokeless sources of nicotine including e-cigarettes and smokeless tobacco, neither of which are associated with cg05575921 demethylation. A combination of methylomic and metabolite profiling may allow for accurate classification use status of a variety of nicotine containing products.

A series of N-acyl derivatives of anabasine and cytisine were prepared, to discover novel, natural product-based medicinal agents. All synthesized compounds were tested for antimicrobial, antifungal, antiviral and analgesic activity. The most pronounced antibacterial activity was shown by the compounds with isoxazole fragments, while the adamantane derivatives showed the greatest antiviral effect. It was found that the majority of anabasine derivatives showed significant analgesic activity, reducing the pain response of animals to the irritating effect of acetic acid. The presence of a high level of antimicrobial and antiviral activity in newly synthesized compounds makes it possible to consider them promising for further study of their pharmacological properties. [ABSTRACT FROM AUTHOR]

[Display omitted] The results of analysis of the thermal decomposition kinetics of inclusion complexes of β-cyclodextrin with the alkaloid anabasine at different heating rates are presented. The kinetic characteristics of the processes are determined based on the Friedman, Flynn–Wall–Ozawa and nonparametric kinetics methods. [ABSTRACT FROM AUTHOR]

The Heck reaction between N‐heteroaryl halides and heterocyclic alkenes provides a convenient approach to biologically relevant α‐heteroaryl functionalized heterocycles, yet reactions of this type have been challenging due to strong N‐heteroaryl coordination to palladium metal, which causes catalyst poisoning. In this report, an efficient palladium‐catalyzed Heck reaction between N‐heteroaryl halides and heterocyclic olefins is established, leading to a variety of α‐heteroaryl substituted heterocycles. The method features an unprecedented broad substrate scope and excellent functional group compatibility. The employment of a sterically bulky P, P=O ligand containing an anthryl moiety is crucial for this transformation due to the coordinative unsaturation facilitated by its steric bulkiness. The asymmetric variant of the Heck reaction is achieved with (S)‐DTBM‐SEGPHOS via a cationic palladium pathway, which has enabled an efficient asymmetric synthesis of (S)‐nicotine and its analogues. [ABSTRACT FROM AUTHOR]

The encapsulation of the famous alkaloid, anabasine, with β-CD was studied to obtain a more stable and bioavailable inclusion complex. Various in silico and experimental studies of the obtained β-CD-anabasine complex are presented. Firstly, molecular docking studies were conducted against the α, β, and γ cyclodextrins to explore which subclass is the best for encapsulation. The obtained results that pointed at β-cyclodextrin were further confirmed by five MD simulations and MM-PBSA studies. Experimentally, the spectral properties of the anabasine β-cyclodextrin complex were determined by FT-IR, 1H, and 13C-NMR spectroscopic methods. Additionally, the surface morphology of the anabasine β-cyclodextrin was investigated using a scanning electron microscope. Furthermore, the outputs of the thermographic measurements utilizing a differential scanning calorimeter were displayed. The activation energy of the reaction of thermo-oxidative destruction of the clathrate complex was calculated, and the kinetic parameters of the thermal destruction processes were decided using the Freeman–Carroll, Sharpe–Wentworth, Achar, and Coates–Redfern methods. The kinetic parameters of the thermal decomposition of the anabasine β-cyclodextrin were in agreement and verified the reliability of the obtained results. The obtained computational, spectral, morphological, and thermogravimetric results verified the successful formation of the anabasine β-cyclodextrin complex. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is an intractable disease that causes persistent colonic inflammation. Numerous studies have reported that smoking can afford clinical benefits in UC. This study aimed to elucidate whether nicotine, the main component in cigarettes, can exert pharmacological effects against experimental UC. To achieve this objective, we compared the effects of nicotine with those of structural nicotine analogs in a UC rodent model (Slc: Wistar rats, male, 9-week-old, and 220–250 g/rat). Nicotine, or a respective structural analog (nornicotine, cotinine, anabasine, myosmine, and anatabine), was administered intraperitoneally daily to rats (n = 6/group) exhibiting dextran sulfate sodium-induced experimental colitis. Examining the colon tissues of model rats, we compared disease severity, cytokine secretion, and α7 nicotine acetylcholine receptor (nAChR7) expression. We observed that nicotine administration induced weight loss at 2.35% in 10 days. Notably, the reduction in histological severity (score) of UC was more pronounced in rats treated with nicotine (score = 4.83, p = 0.042) than in untreated rats (score = 8.17). Nicotine administration increased nAChR7 expression 6.88-fold (p = 0.022) in inflammatory sites of the colon, mainly by suppressing the production of interleukin (IL)-1β and IL-6. Moreover, the secretion of these cytokines was suppressed in lipopolysaccharide-stimulated rat macrophages (MΦ) treated with nicotine. In conclusion, nicotine better alleviates experimental UC than the examined structural analogs by activating nAChR7 expression and suppressing proinflammatory cytokines in MΦ.

Increasing use of non-combusted forms of nicotine such as e-cigarettes poses important public health questions regarding their specific risks relative to combusted tobacco products such as cigarettes. To fully delineate these risks, improved biomarkers that can distinguish between these forms of nicotine use are needed. Prior work has suggested that methylation status at cg05575921 may serve as a specific biomarker of combusted tobacco smoke exposure. We hypothesized combining this epigenetic biomarker with conventional metabolite assays could classify the type of nicotine product consumption. Therefore, we determined DNA methylation and serum cotinine values in samples from 112 smokers, 35 e-cigarette users, 19 smokeless tobacco users, and 269 controls, and performed mass spectroscopy analyses of urine samples from all nicotine users and 22 verified controls to determine urinary levels of putatively nicotine product-specific substances; propylene glycol, 2-cyanoethylmercapturic acid (CEMA), and anabasine. 1) Cigarette smoking was associated with a dose dependent demethylation of cg05575921 and increased urinary CEMA and anabasine levels, 2) e-cigarette use did not demethylate cg05575921, 3) smokeless tobacco use also did not demethylate cg05575921 but was positively associated with anabasine levels 4) CEMA and cg05575921 levels were highly correlated and 5) propylene glycol levels did not reliably distinguish use groups. Cg05575921 assessments distinguish exposure to tobacco smoke from smokeless sources of nicotine including e-cigarettes and smokeless tobacco, neither of which are associated with cg05575921 demethylation. A combination of methylomic and metabolite profiling may allow for accurate classification use status of a variety of nicotine containing products. [ABSTRACT FROM AUTHOR]

Abstract Background Invasive plant species pose a significant threat for fragile isolated ecosystems, occupying space, and consuming scarce local resources. Recently though, an additional adverse effect was recognized in the form of its secondary metabolites entering the food chain. The present study is elaborating on this subject with a specific focus on the Nicotiana glauca Graham (Solanaceae) alkaloids and their occurrence and food chain penetrability in Mediterranean ecosystems. For this purpose, a targeted liquid chromatography electrospray tandem mass spectrometric (LC–ESI–MS/MS) analytical method, encompassing six alkaloids and one coumarin derivative, utilizing hydrophilic interaction chromatography (HILIC) was developed and validated. Results The method exhibited satisfactory recoveries, for all analytes, ranging from 75 to 93%, and acceptable repeatability and reproducibility. Four compounds (anabasine, anatabine, nornicotine, and scopoletin) were identified and quantified in 3 N. glauca flowers extracts, establishing them as potential sources of alien bio-molecules. The most abundant constituent was anabasine, determined at 3900 μg/g in the methanolic extract. These extracts were utilized as feeding treatments on Apis mellifera honeybees, resulting in mild toxicity documented by 16–18% mortality. A slightly increased effect was elicited by the methanolic extract containing anabasine at 20 μg/mL, where mortality approached 25%. Dead bees were screened for residues of the N. glauca flower extracts compounds and a significant mean concentration of anabasine was evidenced in both 10 and 20 μg/mL treatments, ranging from 51 to 92 ng/g per bee body weight. Scopoletin was also detected in trace amounts. Conclusions The mild toxicity of the extracts in conjunction with the alkaloid and coumarin residual detection in bees, suggest that these alien bio-molecules are transferred within the food chain, suggesting a chemical invasion phenomenon, never reported before.

Nemerteans (also called Nemertines) are a phylum of predominantly marine worms that use toxins to capture prey and to defend themselves against predators. Hoplonemerteans have a proboscis armed with one or more stylets used in prey capture and are taxonomically divided into Order Monostilifera, whose members possess a single large proboscis stylet, and Order Polystilifera, whose members have multiple small stylets. Many monostiliferans contain alkaloidal toxins, including anabaseine, that stimulate and then desensitize nicotinic acetylcholine receptors that are present in all animals. These compounds also interact with pyridyl chemoreceptors in crustaceans, reducing predation and larval settlement. Anabaseine has been a lead compound in the design of alpha7 nicotinic acetylcholine receptor agonists like GTS-21 (also called DMXBA) to treat disorders of cognition such as Alzheimer’s disease and schizophrenia. These drug candidates also display anti-inflammatory activities of potential medical importance. Most polystiliferans live deep in open oceans and are relatively inaccessible. We fortunately obtained two live specimens of a large benthic polystiliferan, Paradrepanophorus crassus (Pc), from the coast of Spain. MS and NMR analyses of the Ehrlich’s reagent derivative allowed identification of anabaseine. A spectrophotometric assay for anabaseine, also based on its reaction with Ehrlich’s reagent, revealed high concentrations of anabaseine in the body and proboscis. Apparently, the biosynthetic mechanism for producing anabaseine was acquired early in the evolution of the Hoplonemertea, before the monostiliferan-polystiliferan divergence.

A series of N-acyl derivatives of anabasine and cytisine were prepared, to discover novel, natural product-based medicinal agents. All synthesized compounds were tested for antimicrobial, antifungal, antiviral and analgesic activity. The most pronounced antibacterial activity was shown by the compounds with isoxazole fragments, while the adamantane derivatives showed the greatest antiviral effect. It was found that the majority of anabasine derivatives showed significant analgesic activity, reducing the pain response of animals to the irritating effect of acetic acid. The presence of a high level of antimicrobial and antiviral activity in newly synthesized compounds makes it possible to consider them promising for further study of their pharmacological properties.

[Display omitted] • NMR-based metabolite profiling of a Brazilian endemic desiccation tolerant plant. • Flavonoids could contribute to oxidative stress mitigation in rehydrated plants. • Anabasine: an undescribed alkaloid from a lycophyte. • Selaginella convoluta dry/hydrated: phytochemical richness from semiarid environment. Selaginella convoluta is a Brazilian endemic, desiccation tolerant plant with an effective drought-resistance mechanism. Herein, nuclear magnetic resonance (NMR)-based metabolite profiling was used to investigate this species in different hydration states: dried (harvested in the natural semiarid environment) and after rehydration. NMR is a suitable tool for this analysis because it allows the simultaneous detection of secondary and primary metabolites. To support NMR-based metabolite annotation, an in-house database was built by including all the experimental 1H NMR spectral data reported for the natural products previously identified in Selaginella spp. The analysis criteria were related to spectral similarity values based on the algorithm of pattern recognition between the in-house database and the total correlated spectroscopy (1H-1H TOCSY-NMR) experimental data. The in silico strategy with a similarity threshold of 50 %−100 % between the experimental and virtual spectra enabled the annotation of 86 metabolites. Among these, 49 metabolites showed a spectral similarity of 100 %. Notably, the isolation of the pyridine alkaloid anabasine from S. convoluta shoots and its structural assignment provided new chemical information for lycophytes. The multi-edaphoclimatic features of the Caatinga, an exclusively Brazilian semiarid biome, may contribute to an altered metabolite profile associated with desiccation. [ABSTRACT FROM AUTHOR]

The encapsulation of the famous alkaloid, anabasine, with β-CD was studied to obtain a more stable and bioavailable inclusion complex. Various in silico and experimental studies of the obtained β-CD-anabasine complex are presented. Firstly, molecular docking studies were conducted against the α, β, and γ cyclodextrins to explore which subclass is the best for encapsulation. The obtained results that pointed at β-cyclodextrin were further confirmed by five MD simulations and MM-PBSA studies. Experimentally, the spectral properties of the anabasine β-cyclodextrin complex were determined by FT-IR, 1H, and 13C-NMR spectroscopic methods. Additionally, the surface morphology of the anabasine β-cyclodextrin was investigated using a scanning electron microscope. Furthermore, the outputs of the thermographic measurements utilizing a differential scanning calorimeter were displayed. The activation energy of the reaction of thermo-oxidative destruction of the clathrate complex was calculated, and the kinetic parameters of the thermal destruction processes were decided using the Freeman–Carroll, Sharpe–Wentworth, Achar, and Coates–Redfern methods. The kinetic parameters of the thermal decomposition of the anabasine β-cyclodextrin were in agreement and verified the reliability of the obtained results. The obtained computational, spectral, morphological, and thermogravimetric results verified the successful formation of the anabasine β-cyclodextrin complex.

Orange-tufted sunbirds (Cinnyris osea) feed on the nectar of the tobacco tree (Nicotiana glauca) which contains toxic pyridine alkaloids characterized by high concentrations of anabasine and much lower concentrations of nicotine. We aimed at determining whether the gut microbiota of sunbirds harbors bacterial species that enable the birds to cope with these toxic alkaloids. An in vivo experiment that included 12 birds showed that inducing dysbiosis in sunbirds’ guts by the addition of sulfamethoxazole and trimethoprim, significantly reduced the birds’ ability to degrade anabasine (n = 3) compared to control birds (n = 3) with undisturbed microbiota. Sunbirds whose gut bacterial communities were altered by the antibacterial agents and who were fed with added nicotine, also showed a lower percentage of nicotine degradation (n = 3) in their excreta compared to the sunbirds with undisturbed microbiota (n = 3), though this difference was not significant. In an in vitro experiment, we studied the ability of Lactococcus lactis, Enterobacter hormaechei, Chryseobacterium gleum, Kocuria palustris, and Methylorubrum populi that were isolated from sunbirds’ excreta, to degrade anabasine and nicotine. By using gas chromatography-mass spectrometry (GC-MS) analysis, we successfully demonstrated, for the first time, the ability of these species to degrade the focal secondary metabolites. Our findings demonstrate the role of gut bacteria in detoxifying toxic secondary metabolites found in the N. glauca nectar. The degradation products may supply the birds with nitrogen which is scarce in nectar-rich diets. These findings support another role of bacteria in mediating the interactions between plants and their pollinators.

Orange-tufted sunbirds (Cinnyris osea) feed on the nectar of the tobacco tree (Nicotiana glauca) which contains toxic pyridine alkaloids characterized by high concentrations of anabasine and much lower concentrations of nicotine. We aimed at determining whether the gut microbiota of sunbirds harbors bacterial species that enable the birds to cope with these toxic alkaloids. An in vivo experiment that included 12 birds showed that inducing dysbiosis in sunbirds' guts by the addition of sulfamethoxazole and trimethoprim, significantly reduced the birds' ability to degrade anabasine (n = 3) compared to control birds (n = 3) with undisturbed microbiota. Sunbirds whose gut bacterial communities were altered by the antibacterial agents and who were fed with added nicotine, also showed a lower percentage of nicotine degradation (n = 3) in their excreta compared to the sunbirds with undisturbed microbiota (n = 3), though this difference was not significant. In an in vitro experiment, we studied the ability of Lactococcus lactis , Enterobacter hormaechei , Chryseobacterium gleum , Kocuria palustris , and Methylorubrum populi that were isolated from sunbirds' excreta, to degrade anabasine and nicotine. By using gas chromatography-mass spectrometry (GC-MS) analysis, we successfully demonstrated, for the first time, the ability of these species to degrade the focal secondary metabolites. Our findings demonstrate the role of gut bacteria in detoxifying toxic secondary metabolites found in the N. glauca nectar. The degradation products may supply the birds with nitrogen which is scarce in nectar-rich diets. These findings support another role of bacteria in mediating the interactions between plants and their pollinators. [ABSTRACT FROM AUTHOR]

Measurement of population tobacco use via wastewater-based epidemiology (WBE) provides objective data to evaluate the efficacy of tobacco control strategies. However, current WBE tobacco-use estimates based on nicotine metabolites (cotinine and hydroxycotinine) can be masked by use of non-tobacco nicotine-containing products. To better understand nicotine and tobacco use, we analysed tobacco-specific biomarkers, anabasine and anatabine, as well as nicotine metabolites, cotinine and hydroxycotinine, in wastewater samples collected for 6 weeks per year over 6 years (2012–2017) from an Australian wastewater treatment plant serving approximately 100,000 people. Population-normalised mass loads were used to estimate tobacco and nicotine use trends and were compared with surveys and taxation statistics. Significant annual declines were observed for anabasine, anatabine, cotinine and hydroxycotinine of −3.0%, −2.7%, −2.4%, and −2.1%, respectively. The results corresponded with the annual declining trends reported from surveys (−5%) and taxation statistics (−4%). Significant annual decreases in the ratios of anabasine to cotinine (−1.2%) and anatabine to cotinine (−1.0%) suggested a relative increase in the use of non-tobacco nicotine products at the same time that tobacco use was declining. Monitoring tobacco use with anabasine and anatabine removed influence from nicotine-containing products, showing larger reductions in this Australian city than via nicotine biomarkers, whilst also demonstrating their suitability for monitoring long-term trends.

The reactions of cytisine with glycidyl ethers of 3-arylcoumarins were studied. A series of cytisine–coumarin conjugates were synthesized via regiospecific opening of the oxirane ring by cytisine. Methods for conjugating anabasine and cytisine with 3-arylcoumarins through a but-2-ynyl linker via reactions of propargyl ethers of 7-hydroxy- and 6-hydroxy-3-arylcoumarins with the alkaloids were proposed. [ABSTRACT FROM AUTHOR]

Anabasine (ANA), a major piperidine alkaloid originally isolated from wild tobacco trees (Nicotiana glauca), has been known to induce serious developmental toxicities such as skeletal deformities in livestock and humans. In this study, we thoroughly investigated the supramolecular nano-encapsulations of ANA by an artificial nanocontainer, cucurbit[7] uril (CB[7]), and examined the influences of the nano-encapsulation on ANA's inherent developmental toxicities on a zebrafish model. We have shown that CB[7] formed 1:1 host-guest inclusion complexes with ANA via a relatively high binding strength [Ka of (7.45 ± 0.31) × 104 M−1] in an aqueous solution, via UV-vis and 1H nuclear magnetic resonance spectroscopic titrations, as well as isothermal titration calorimetry titration. As a consequence, CB[7] significantly attenuated the developmental toxicity of ANA on zebrafish in vivo. In contrast, for a comparative purpose, β-CD didn't exert any influence on the toxicity of ANA due to its weak binding with ANA, which was not even measurable via either spectroscopic methods or ITC titration. This is the first head-to-head comparison of this pair of nanocontainers, CB[7] and β-CD, on their potential roles in influencing the toxicity of guest molecules and the results suggested that CB[7] could become a more promising functional excipient for reducing the inherent toxicities of active pharmaceutical ingredients, particularly alkaloids that may form relatively strong host-guest binding species with the host.

The reaction of nucleophilic substitution of 2-chloro-N-(6-methyl-2-oxo-4-phenyl-1,2-dihydropyridin-3-yl)acetamide and 2-(chloromethyl)-5-methyl-7-phenyloxazolo[5,4-b]pyridine with cytisine, anabasine, and salsoline alkaloids has afforded the corresponding derivatives. Structure of the obtained compounds has been confirmed by means of 1H and 13C NMR spectroscopy. [ABSTRACT FROM AUTHOR]

Ethnopharmacology Relevance: Crossbow-medicine needle therapy (microneedle roller combined with crossbow-medicine) is one of the external treatment methods of Miao Medicine in China. It is a way of combining acupuncture with Chinese herbal medicine, which is widely used in clinical treatment of pain., Aim of the Study: To observe the transdermal absorption promoting effect of microneedle roller via transdermal administration, and to discuss the transdermal absorption characteristics and the safety of crossbow-medicine needle therapy., Methods: Based on the determination of the content of the main components of crossbow-medicine prescription in our previous research, the present experiment was conducted in-vitro and in-vivo experiments and the skin of rats was used as the penetration barrier. For in-vitro experiment, the modified Franz diffusion cell method was used to determine the transdermal absorption rate and 24h cumulative transdermal absorption amount of the active ingredients of crossbow-medicine liquid. For in-vivo experiment, tissue homogenization was applied to compare the skin retention amount and plasma concentration of crossbow-medicine liquid absorbed at different time points via the aforementioned two modes of administration. Furthermore, the effect of crossbow-medicine needle on the morphological structure of rat skin stratum corneum was detected by hematoxylin-eosin (HE) staining. The safety of crossbow-medicine needle therapy was evaluated according to the scoring criteria of the skin irritation test., Results: 1. In-vitro experiment: In the microneedle-roller group and crossbow-medicine liquid application group, the effect of transdermal delivery was identified in all the four ingredients of anabasine, chlorogenic acid, mesaconitine and hypaconitine. The 24h cumulative transdermal absorption amount and transdermal absorption rate of each ingredient in microneedle-roller group were significantly higher than those in crossbow-medicine liquid application group (all P < 0.05). 2. In-vivo experiment: Both microneedle-roller and crossbow-medicine liquid application could promote the transdermal absorption of the active ingredients of the drug in the skin and retain in the skin structure. After 8h of administration, the total retention amount of anabasine, chlorogenic acid, mesaconitine and hypaconitine in the skin of rats in the former group was significantly higher than that in the latter group (all P < 0.05). 3. HE staining: In the blank group, the stratum corneum showed an evenly zonal distribution on the active epidermis, and had a close connection with the epidermis, without exfoliation or cell dissociation of the stratum corneum. The crossbow-medicine liquid group had a relatively complete stratum corneum, with a small proportion of exfoliation or cell dissociation, loose arrangement and loose connection with the epidermis. In the microneedle-roller group, the skin had pore channels, and the stratum corneum was loose and exfoliated, which showed zonal distribution in a free state and a high degree of separation. The crossbow-medicine needle group had loose the stratum corneum, broken and exfoliated, which was separated from the active epidermis and showed zonal distribution in a free state. 4., Safety: No obvious erythema, edema and skin protuberance were observed in the skin of rats treated with microneedle roller, crossbow-medicine liquid and crossbow-medicine needle. Additionally, the skin irritative response score was 0., Conclusion: Microneedle roller can promote the transdermal absorption of crossbow-medicine liquid, and crossbow-medicine needle therapy has good safety., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

OBJECTIVES:This study (1) determined levels of various tobacco alkaloids in commercial tobacco products. (2) determined urinary concentrations, urinary excretion, and half-lives of the alkaloids in humans; and (3) examined the possibility that urine concentrations of nicotine-related alkaloids can be used as biomarkers of tobacco use. METHODS:Nicotine intake from various tobacco products was determined through pharmacokinetic techniques. Correlations of nicotine intake with urinary excretion and concentrations of anabasine, anatabine, nornicotine, nicotine, and cotinine were examined. By using urinary excretion data, elimination half-lives of the alkaloids were calculated. RESULTS:Alkaloid levels in commercial tobacco products, in milligrams per gram, were as follows: nicotine, 6.5 to 17.5; nornicotine, 0.14 to 0.66; anabasine, 0.008 to 0.030; and anatabine, 0.065 to 0.27. Measurable concentrations of all alkaloids were excreted in the urine of most subjects smoking cigarettes, cigars, and pipes and using smokeless tobacco. Correlations between nicotine intake and alkaloid concentrations were good to excellent. CONCLUSIONS:Anabasine and anatabine, which are present in tobacco but not in nicotine medications, can be used to assess tobacco use in persons undergoing nicotine replacement therapy.

The chiral homoallylamines with orthogonal bifunctional handle, an amine, and a pendant allyl unit are available to be easily converted into N-heterocycles. The N-allylation and Ru-catalyzed ring-closing metathesis delivered the bioactive 2-arylpiperidines, Nicotiana tabacum alkaloids (R)-anatabine and (R)-anabasine in three steps. A formal synthesis of (R)-N-methylanatabine and (R)-N-methylanabasine is also completed. [ABSTRACT FROM AUTHOR]

The reactions of the cytisine and anabasine alkaloids with cinnamic acid chloride have been studied, and hydrazinolysis of the resulting N-cinnamoylcytisine and N-cinnamoylanabazine has been carried out. The reaction of cinnamoyl isothiocyanate with alkaloids has afforded the corresponding thiourea derivatives. Antimicrobial and cytotoxic activity of cinnamoyl-containing derivatives of these alkaloids has been evaluated. [ABSTRACT FROM AUTHOR]

In the following paper, we present the results of our studies on the interactions of the Aβ1-42 peptide and its three short fragments, namely Aβ5-16 (RHDSGYEVHHQK; HZ1), Aβ8-13 (SGYEVH; HZ2), and Aβ8-12 (SGYEV; HZ3) with selected painkillers (ibuprofen and aspirin) and compounds of natural origin (anabasine and epinephrine). Steady-state fluorescence spectroscopy was used to study the binding properties of the selected systems. Additionally, based on molecular dynamics (MD) calculations supported by NMR-derived restrains, we have proposed the most likely area of the interactions of Aβ1-42 and Aβ5-16 peptides with the investigated compounds. The influence of symmetrically oriented side chains of amino acid residues present in the first part of the Aβ1-42 sequence on the stability of the resulting complexes has been discussed. Finally, the changes in the peptide structures on account of complex formation were analyzed.

Many organisms possess “secondary” compounds to avoid consumption or to immobilize prey. While the most abundant or active compounds are initially investigated, more extensive analyses reveal other “minor” compounds with distinctive properties that may also be of biomedical and pharmaceutical significance. Here, we present an initial in vitro investigation of the actions of two isomeric tetrahydropyridyl ring-containing anabasine analogs: isoanatabine, an alkaloid isolated from a marine worm, and anatabine, a relatively abundant minor alkaloid in commercial tobacco plants. Both compounds have a double bond that is distal to the piperidine ring nitrogen of anabasine. Racemic isoanatabine and anatabine were synthesized and their S- and R-enantiomers were isolated by chiral high pressure liquid chromatography (HPLC). Both isoanatabines displayed higher efficacies at α4β2 nicotinic acetylcholine receptors (nAChRs) relative to the anatabines; R-isoanatabine was most potent. Radioligand binding experiments revealed similar α4β2 nAChR binding affinities for the isoanatabines, but R-anatabine affinity was twice that of S-anatabine. While the two anatabines and S-isoanatabine were highly efficacious agonists at α7 nAChRs, R-isoanatabine was only a weak partial agonist. The four compounds share an ability to stimulate both α4β2 and α7 nAChRs, a property that may be useful in developing more efficacious drugs to treat neurodegenerative and other medical disorders.

Possible Mannich aminomethylation of isoflavone chromone rings was studied using the alkaloid anabasine. Anabasine-isoflavone conjugates in which the benzopyrone core was connected to anabasine through a methylene linker were synthesized. [ABSTRACT FROM AUTHOR]

Concerns over the harmful effects of synthetic insecticides have stimulated interest in alternative pest management tactics including botanical insecticides that provide novel modes of action against pests that have developed resistance against synthetic insecticides. Much work has been conducted using plants native to various developing countries but the Australian flora has been little explored as a source of novel plant protection treatments. Here we report potent insecticidal properties of the Australian plant, native tobacco Nicotiana megalosiphon against three key pests of brassicas: the diamondback moth ( Plutella xylostella ), cabbage aphid ( Brevicoryne brassicae ) and the green peach aphid ( Myzus persicae ). Aqueous extracts (1%, 5% and 10% w/v) of N. megalosiphon gave up to 100% control of P. xylostella ; better than the recommended rate of tau-fluvalinate (a synthetic pyrethroid) or equivalent extracts of a second Australian native plant, Mentha satureioides. Treatment with N. megalosiphon also gave 100% control of B. brassicae at the highest two concentrations, and of M. persicae at the highest concentration. In a second study using F1 P. xylostella survivors of tau-fluvalinate treatment, the highest two rates of N. megalosiphon caused 100% mortality though efficacy of tau-fluvalinate was eroded compared with use on the previous generation. Chemical analysis of N. megalosiphon recorded the presence of anabasine at 5.2 μg/ml in water extracts of leaves and 59.4 μg/ml in methanol extracts of leaves. While these concentrations were low particularly for the water extracts they might nevertheless explain the biological activity of N. megalosiphon . [ABSTRACT FROM AUTHOR]

Aims: To assess whether bottles of refill liquids for e-cigarettes were filled true to label, whether their content was constant across two production batches, and whether they contained impurities.Methods: In 2013, we purchased on the Internet 18 models from 11 brands of e-liquids. We purchased a second sample of the same models 4months later. We analyzed their content in nicotine, anabasine, propylene glycol, glycerol, ethylene glycol and diethylene glycol, and tested their pH.Results: The median difference between the nicotine value on the labels and the nicotine content in the bottles was 0.3mg/mL (range -5.4 to +3.5mg/mL, i.e. -8% to +30%). For 82% of the samples, the actual nicotine content was within 10% of the value on the labels. All models contained glycerol (median 407mg/mL), and all but three models contained propylene glycol (median 650mg/mL). For all samples, levels of anabasine, ethylene glycol and diethylene glycol were below our limits of detection. The pH of all the e-liquids was alkaline (median pH=9.1; range 8.1 to 9.9). The measured content of two batches of the same model varied by a median of 0% across batches for propylene glycol, 1% for glycerol, 0% for pH, and 0.5% for nicotine (range -15% to +21%; 5th and 95th percentiles: -15% and +10%).Conclusions: The nicotine content of these e-liquids matched the labels on the bottles, and was relatively constant across production batches. The content of propylene glycol and glycerol was also stable across batches, as was the pH. [ABSTRACT FROM AUTHOR]

Tobacco smoking remains an important public health issue worldwide. Assessment of exposure to tobacco-related toxicants and carcinogens at the population level is thus an essential population health indicator. This can be achieved by wastewater-based epidemiology (WBE), which relies on the analysis of biomarkers in wastewater. However, required analytical methods for the simultaneous measurement of tobacco-related toxicants and carcinogens in wastewater are not available. In this study, a new analytical procedure was developed and validated to measure tobacco-related alkaloids, carcinogens, and their metabolites in raw wastewater, including anabasine (ANABA), anatabine (ANATA), cotinine (COT), trans-3'-hydroxycotinine (COT-OH), N-nitrosoanabasine (NAB), N-nitrosoanatabine (NAT), N-nitrosonornicotine (NNN), 4-(methylnitrosamino) -1-(3-pyridyl)-1-butanone (NNK), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), NNAL-N-β-glucuronide, and NNAL-O-β-glucuronide. Different parameters were optimized for the solid-phase extraction procedure and instrumental analysis using liquid chromatography-tandem mass spectrometry. The optimized method was fully validated, resulting in acceptable within-run and between-run precision (<8% and <10% relative standard deviation, respectively) and accuracy (<9% and <13% bias, respectively). Method quantification limits were at 0.5-120 ng/L in wastewater. Target analytes were stable in wastewater at 4 and 20 °C over 24 h. The developed method was applied to wastewater samples from two Belgian cities. Average concentrations of COT, COT-OH, ANATA, ANABA, and NAT were 5200, 2600, 30, 10, and 0.6 ng/L, respectively, while NAB, NNN, NNK, and NNAL were not detected in the samples. With the developed robust analytical method, our study provided the first insight into the population exposure to both toxicants and carcinogens resulting from tobacco use. [ABSTRACT FROM AUTHOR]

Background: Floral phytochemicals are ubiquitous in nature, and can function both as antimicrobials and as insecticides. Although many phytochemicals act as toxins and deterrents to consumers, the same chemicals may counteract disease and be preferred by infected individuals. The roles of nectar and pollen phytochemicals in pollinator ecology and conservation are complex, with evidence for both toxicity and medicinal effects against parasites. However, it remains unclear how consistent the effects of phytochemicals are across different parasite lineages and environmental conditions, and whether pollinators actively self-medicate with these compounds when infected. Approach: Here, we test effects of the nectar alkaloid anabasine, found in Nicotiana, on infection intensity, dietary preference, and survival and performance of bumble bees (Bombus impatiens). We examined variation in the effects of anabasine on infection with different lineages of the intestinal parasite Crithidia under pollen-fed and pollen-starved conditions. Results: We found that anabasine did not reduce infection intensity in individual bees infected with any of four Crithidia lineages that were tested in parallel, nor did anabasine reduce infection intensity in microcolonies of queenless workers. In addition, neither anabasine nor its isomer, nicotine, was preferred by infected bees in choice experiments, and infected bees consumed less anabasine than did uninfected bees under no-choice conditions. Furthermore, anabasine exacerbated the negative effects of infection on bee survival and microcolony performance. Anabasine reduced infection in only one experiment, in which bees were deprived of pollen and post-pupal contact with nestmates. In this experiment, anabasine had antiparasitic effects in bees from only two of four colonies, and infected bees exhibited reduced—rather than increased—phytochemical consumption relative to uninfected bees. Conclusions: Variation in the effect of anabasine on infection suggests potential modulation of tritrophic interactions by both host genotype and environmental variables. Overall, our results demonstrate that Bombus impatiens prefer diets without nicotine and anabasine, and suggest that the medicinal effects and toxicity of anabasine may be context dependent. Future research should identify the specific environmental and genotypic factors that determine whether nectar phytochemicals have medicinal or deleterious effects on pollinators. [ABSTRACT FROM AUTHOR]

The present work represents a novel approach using earwax (cerumen) for the evaluation of the smoking status with regards to tobacco use/exposure. The method utilizes the difference in the concentration profiles of nicotine and its related compounds in earwax to discriminate among non-, passive, and active smokers. Earwax samples were collected from three study groups (non-, passive, and active smokers) and subjected to analysis by headspace gas chromatography-mass spectrometry. The nicotine levels in earwax were much lower than cotinine levels, even for active smokers; however, it was reported that the nicotine levels in scalp hair were much higher than the cotinine levels. Therefore, it is obviously correct that earwax is protected from external contamination to a larger extent than expected. The concentration profiles of nicotine and its related compounds ( o-nicotine, cotinine, and anabasine) in the analyzed earwax samples were treated by data mining techniques. It was possible to discriminate the studied groups using the evolutionary tree (evtree) algorithm and support vector machine discriminant analysis as the statistical models with the best discrimination accuracies of 96.7 and 95.0%, respectively. The analytical method applied requires no sample pretreatment which makes it easy, fast, and a low-cost alternative method to those employing other biological matrices, such as blood, urine, and hair. The earwax, which is considered a neglected body secretion, is a useful tool to determine the exposure to tobacco smoke noninvasively and without the influence of external contamination. [ABSTRACT FROM AUTHOR]