Inhibition of mutagenicity of N-nitrosamines by tobacco smoke and its constituents

Tobacco smoke is a complex chemical mixture including pyridine alkaloids and N-nitrosamines, with the concentration of the former several orders of magnitude higher than that of the N-nitrosamines. The major biologically important N-nitrosamines present in tobacco smoke are N-nitrosodimethylamine (NDMA), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and N-nitrosonornicotine (NNN). These nitrosamines require metabolic activation by cytochrome P-450s for the expression of mutagenicity. Although nicotine, the major pyridine alkaloid in tobacco, has been shown to inhibit the metabolic activation of NNK, its effect on the mutagenicity of NNK and other N-nitrosamines has not been reported. In the present study, the ability of three pyridine alkaloids (nicotine, cotinine, nornicotine) and aqueous cigarette smoke condensate extract (ACE) to inhibit the mutagenicity of tobacco-related N-nitrosamines was tested on Salmonella typhimurium strain TA1535 in the presence of a metabolic activation system (S9). All three of the pyridine alkaloids tested, as well as ACE, inhibited the mutagenicity of NDMA and NNK, but not NNN, in a concentration-dependent manner. The induction of SCEs in mammalian cells (CHO) by NNK in the presence of metabolic activation was also significantly reduced by nicotine and cotinine. None of the observed reductions in mutagenicity could be explained by cytotoxicity. These results demonstrate that tobacco smoke contains chemicals, pyridine alkaloids and other unidentified constituent(s), which inhibit the mutagenicity of N-nitrosamines.     

Four new diterpenoid alkaloids from Delphinium elatum

Diterpenoid alkaloids exhibit remarkable chemical properties and biological activities. Such compounds are frequently found in plants of the genera Aconitum, Delphinium, and Garrya. Several diterpenoid alkaloid components from Delphinium elatum cv. Pacific Giant and their derivatives exhibited cytotoxic activity against lung, prostate, nasopharyngeal, and vincristine-resistant nasopharyngeal cancer cell lines. Phytochemical investigations on the seeds of D. elatum cv. Pacific Giant led to the isolation of four new C₁₉-diterpenoid alkaloids, melpheline (1), 19-oxoisodelpheline (2), N-deethyl-19-oxoisodelpheline (3), and N-deethyl-19-oxodelpheline (4). The isolated alkaloids were elucidated by extensive spectroscopic methods including NMR (1D and 2D), IR, and MS (HRMS).     

Concomitant occurrence of pyrrolizidine and quinolizidine alkaloids in the hemiparasite Osyris alba L. (Santalaceae)

The investigation of the alkaloid extracts of the hemiparasitic plant Osyris alba, collected from three different localities in southern France, revealed the concomitant presence of both pyrrolizidine (PA) and quinolizidine (QA) alkaloids in the samples from two of these localities. The sample from the third locality contained only PAs. The eight QAs identified were sparteine, N-methylcytisine, cytisine, methyl-12-cytisine acetate, hydroxy-N-methylcytisine, N-acetylcytisine, lupanine, and anagyrine. Of the eleven detected PAs, eight were identified as chysin A, chysin B, 1-carboxypyrrolizidine-7-olide, senecionine, integerrimine, retrorsine, senecivernine and a new alkaloid janfestine (7R-hydroxychysin A or 1R-carbomethoxy-7R-hydroxypyrrolizidine). PAs were mainly present as their N-oxides This is, to our knowledge, the first report demonstrating the simultaneous presence of two classes of alkaloids, quinolizidine and pyrrolizidine alkaloids, in a single parasitic plant. As these alkaloids do not occur in the same host plant, the results indicate that Osyris must have tapped more than one host plant concomitantly. Since both quinolizidine and pyrrolizidine alkaloids serve as defence compounds against herbivores, affecting different molecular targets, the simultaneous acquisition of the two types of alkaloids by a single plant could provide a novel mode of defence of hemiparasites against herbivores.     

Alkaloids as inhibitors of photophosphorylation in spinach chloroplasts

A group of 12 alkaloids were tested as inhibitors of photophosphorylation in spinach chloroplasts. Ajmaline, a dihydroindole alkaloid, was found to be the strongest inhibitor of both cyclic and non-cyclic photophosphorylation. Low concentrations of ajmaline also inhibited the dark and light ATPases, and the coupled electron flow from water to ferricyanide, measured either as ferrocyanide formed or as oxygen evolved, but not the uncoupled electron transport or the pH rise of illuminated unbuffered suspensions of chloroplasts. Higher concentrations of ajmaline stimulated, instead of inhibiting, photosynthetic electron transport or oxygen evolution and decreased the pH rise, thus behaving as an uncoupler, such as ammonia.Photophosphorylation was partially inhibited by 100 μM dihydrosanguinarine, 100 μM dihydrochelerythrine (benzophenanthridine alkaloids); 500 μM O,O'-dimethylmagnoflorine, 500 μM N-methylcorydine (aporphine alkaloids) and 1 mM julocrotine. They also inhibited coupled oxygen evolution and only partially (dihydrosanguinarine and dihydrochelerythrine) or not at all (the other alkaloids) uncoupled oxygen evolution.Spegazzinine (dihydroindole alkaloid), magnoflorine, N-methylisocorydine, coryneine (aporphine alkaloids), candicine and ribalinium chloride were without effect on photophosphorylation at 500 μM.     

Acridone alkaloids from Severinia buxifolia

Two new acridone alkaloids, severifoline and N-methylseverifoline along with the known alkaloids, N-methylatalaphylline, atalaphyllinine and 5-hydroxy-N-methylseverifoline, were isolated from the root bark of Severinia buxifolia. The structures of severifoline and N-methylseverifoline were established by chemical and spectroscopic methods.     

β-Phenethylamine,tetrahydroisoquinoline and indole Alkaloids of Desmodium tiliaefolium

Ten alkaloids (I-X), five β-phenethylamines, two tetrahydroisoquinolines, and three indole-3-alkylamines, have been isolated from Desmodium tiliaefolium. Chemical transformations, spectral (UV,IR, NMR, MS) evidence, and in most cases comparison with reference materials established their identity as tyramine (I), hordenine (II), 3,4-dimethoxy-β-phenethylamine (III), N,N- dimethyl-3,4-dimethoxyphenethylamine (IV), N-methyl-3,4-dimethoxy-β-hydroxyphenethylamine (V), salsoline (V1), salsolidine (VII), tryptamine (VIII), abrine (IX), and hypahorine (X). Alkaloid (V) is a new naturally occurring compound, while no tetrahydroisoquinoline alkaloid has been encountered before in this genus. This is the first time that three different types of alkaloids have been reported in a single legume species. In addition to the above alkaloids, four quaternary β-phenethylamines and tetrahydroisoquinoline alkaloids have been detected, and choline and betaine have been isolated from the water-soluble alkaloid fraction of the roots.     

Bis-benzylisoquinoline alkaloids from Abuta pahni

From the stems of Abuta pahni, eight isoquinoline alkaloids were isolated and identified by spectroscopic methods and chemical correlations. Three of the bis-benzylisoquinoline alkaloids are new and were assigned the structures 2′-N-nordaurisoline, 2-N-methyllindoldhamine and 2′-N-methyllindoldhamine. The other known alkaloids were coclaurine, daurisoline, lindoldhamine, dimethyllindoldhamine, stepharine and thalifoline.     

Morphinandienone and aporphine alkaloids from Corydalis decumbens

Phytochemical examination of Corydalis decumbens has afforded two new morphinandienone alkaloids, namely, (-)-pallidine N-oxide (1) and (-)-salutaridine N-oxide (2), together with one known analogue, (-)-pallidine (3), and three known aporphine alkaloids (4−6). Their structures were elucidated via comprehensive spectroscopic analysis and chemical correlation. This study represents the first isolation of morphinandienone alkaloids from the title plant. All isolates were tested for their activities towards neuronal excitability in primary cultured neocortical neurons.     

Alkaloids from Galanthus rizehensis

Two new Amaryllidaceae alkaloid N-oxides, incartine N-oxide (1) and lycorine N-oxide (2) together with one β-carboline alkaloid, 1-acetyl-β-carboline (3) and six known alkaloids namely, incartine (4), N-trans feruloyltyramine (5), lycorine (6), O-methylnorbelladine (7), vittatine (8) and 11-hydroxyvittatine (9) were isolated from Galanthus rizehensis Stern (Amaryllidaceae). The structures of the alkaloids were elucidated by spectroscopic analyses (UV, IR, MS, 1D and 2D NMR). Acetylcholinesterase inhibitory activity potentials of the compounds were also determined.     

Metabolic profiling in Echium plantagineum: presence of bioactive pyrrolizidine alkaloids and napthoquinones from accessions across southeastern Australia

Geographically distinct populations of Paterson’s curse (Echium plantagineum L., Boragineacea), found near roadsides across New South Wales and Victoria, Australia were surveyed along 3 distinct longitudinal transects in spring of 2011 for presence of pyrrolizidine alkaloids and naphthoquinones in sampled plants. Composite samples of shoots and roots were collected from each of 45 sites; shoot extracts were subjected to solid phase extraction and LC-ESI/MS for determination of pyrrolizidine alkaloids (PAs) and related N-oxides (PANOs), while root periderm extracts were analysed for naphthoquinone content spectrophotometrically and by LC-ESI/MS. Metabolic profiling of 12 possible PAs and PANOs showed their consistent appearance in all shoot extracts, with lepthamine N-oxide, echimidine-N oxide and echumine N-oxide predominant. The three major PANOs were significantly higher in northern sampling locations than those further south. Root extracts contained shikonin and several related naphthoquinones, as well as two of the major PANOs found in the leaves. Naphthoquinones were highest in the northwest corner of the sampled region. The patterns of abundance of secondary metabolites in E. plantagienum suggest that climate change might result in greater production of defensive compounds by E. plantagineum, making this weed increasingly toxic to livestock.     

Support for the removal of Cyclolobium from tribe Millettieae (Leguminosae) from its quinolizidine alkaloid status

Fruits of Cyclolobium brasiliense Benth. (Leguminosae; Papilionoideae) were found to contain quinolizidine alkaloids. Several tetracyclic sparteine-type alkaloids, the bipiperidyl alkaloid ammodendrine and the α-pyridone alkaloid N-methylcytisine were identified. The presence of quinolizidine alkaloids in this monotypic genus supports a relationship with tribe Brongniartieae and genistoid tribes rather than its current placement in tribe Millettieae.     

Quinoline and indolopyridoquinazoline alkaloids from Vepris louisii

The structures of two new 2-quinolone alkaloids from the stem bark of Vepris louisii, N-methylpreskimmianine [7,8 - dimethoxy - 3 - (3 - methylbut - 2 - enyl) - 1 - methyl - 2 - quinolone] and veprisine (7,8 - dimethoxy - N - methylflindersine) have been deduced from their spectral data and confirmed by partial synthesis from known compounds. Two minor indolopyridoquinazoline alkaloids were also isolated and identified as the already known 1-hydroxyrutaecarpine and the hitherto unknown 7,8-dehydro derivative of 1-hydroxyrutaecarpine.     

New alkaloids from Strychnos icaja

The alkaloids of Strychnos icaja (Loganiaceae) have been studied. An extract from Zaire leaf material yielded nine alkaloids, comprising novacine, the new base 21,22-α-epoxy-4,14-dihydroxy-3-methoxy-N-methyl-sec.-pseudostrychnine, and seven others of known structure previously obtained from the plant. Cameroun leaf material gave five alkaloids, of which one, 21,22-α-epoxy-3,4-dimethoxy-N-methyl-sec.-pseudostrychnine, is new. Fruits from Gabon afforded eight alkaloids; two of them are new and are formulated as 21,22-α-epoxy-4-methoxy-N-methyl-sec.-pseudostrychnine and the corresponding 14-hydroxy derivative.     

Alkaloid constituents from flower buds and leaves of sacred lotus (Nelumbo nucifera,Nymphaeaceae) with melanogenesis inhibitory activity in B16 melanoma cells

Methanolic extracts from the flower buds and leaves of sacred lotus (Nelumbo nucifera, Nymphaeaceae) were found to show inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells. From the methanolic extracts, a new alkaloid, N-methylasimilobine N-oxide, was isolated together with eleven benzylisoquinoline alkaloids. The absolute stereostructure of the new alkaloid was determined from chemical and physicochemical evidence. Among the constituents isolated, nuciferine, N-methylasimilobine, (?)-lirinidine, and 2-hydroxy-1-methoxy-6a,7-dehydroaporphine showed potent inhibition of melanogenesis. Comparison of the inhibitory activities of synthetic related alkaloids facilitated characterization of the structure-activity relationships of aporphine- and benzylisoquinoline-type alkaloids. In addition, 3–30 μM nuciferine and N-methylasimilobine inhibited the expression of tyrosinase mRNA, 3–30 μM N-methylasimilobine inhibited the expression of TRP-1 mRNA, and 10–30 μM nuciferine inhibited the expression of TRP-2 mRNA.     

Isolation and structural characterization of new piperidine alkaloids from Prosopis affinis

The isolation of three new N-methylated piperidine-3-ol alkaloids from the bark of Prosopis affinis Spreng. (Ñandubay) is described. Together with MS and IR data, results from 1D and 2D NMR experiments allowed for the identification of N‑methyl-2-isocassine, N‑methyl-6-isocassine, and N‑methyl-6-isocarnavaline. Inspection of 1D-NOESY spectra and coupling constant data revealed that the heterocyclic moiety of the alkaloids is in fast conformational equilibrium in solution, and this behavior had to be taken into account in order to determine the relative configuration of the chiral centers of the piperidine rings.     

Isoquinoline-derived alkaloids from the bark of Guatteria olivacea (Annonaceae)

Phytochemical investigation of the bark of Guatteria olivacea R. E. Fries (Annonaceae) led to the isolation and identification of ten isoquinoline-derived alkaloids, including three phenanthrenes, atherosperminine, argentinine, and atherosperminine N-oxide; three aporphines, asimilobine, puterine, and discoguattine; two oxoaporphines, liriodenine and oxoputerine; and two tetrahydroprotoberberines, corypalmine and discretine. All these alkaloids are described for the first time in G. olivacea and their chemotaxonomic significance was discussed. The structure elucidation of these isolated alkaloids was established by extensive analyses of 1D and 2D NMR spectroscopy in combination with MS. The NMR data for atherosperminine, argentinine, and atherosperminine N-oxide were reviewed.     

Dereplication of Palicourea sessilis ethanol extracts by UPLC-DAD-ESI-MS/MS discloses the presence of hydroxycinnamic acid amides and the absence of monoterpene indole alkaloids

Secondary metabolites characterization of ethanol extracts of Palicourea sessilis leaves and stems by UPLC-DAD-ESI-MS/MS led to putative identification of hydrolysable tannins in leaf extract (ESI negative mode) while hydroxycinnamic acid amides (HCA) such as N-p-coumaroylputrescine and N-feruloylagmatine were detected in both leaf and stems extracts in the ESI positive mode. Secondary metabolites quantification data showed a higher content of total phenolic in the leaf extract while the total alkaloids contents are statistically equivalent in both of the extracts. Furthermore, monoterpene indole alkaloids were not detected in both extracts. The presence of HCA is here firstly reported for a Palicourea species. This finding increases the classes of secondary metabolites occurring in this genus.     

New immunomodulatory steroidal alkaloids from Sarcococa saligna

Two new steroidal alkaloids, (20 S)-(bennzamido)-3β-(N,N-dimethyamino)-pregnane (1), and (20 S)-(bennzamido)-pregnane-3-one- (2), and two known steroidal alkaloids, pachysanaximine A (3) and 3β, 20α-diacetamido-5α-pregnane (4) were isolated from the whole plant of Sarcococca saligna. The structures of these compounds were identified with the help of spectroscopic techniques while spectra for known compounds were compared with spectra reported in literature. The immunomodulatory potential of the new compounds were found to be significant and dose dependent. Compound 1 showed inhibition of T cells proliferation at 10 μg/mL (95%), and inhibition of IL-2 production with an IC50 = 1.6 μg/mL.     

Senecionine n-oxide,the primary product of pyrrolizidine alkaloid biosynthesis in root cultures of Senecio vulgaris

Root cultures of Senecio vulgaris synthesize pyrrolizidine alkaloids which are accumulated in the form of their N-oxides. The cultures incorporate biosynthetic precursors, such as arginine, ornithine, isoleucine, putrescine and spermidine, with high efficiency into the alkaloids. Senecionine N-oxide is found to be the primary product of biosynthesis. With putrescine and spermidine incorporation rates of 20–30% are obtained. The N-oxide synthesized does not appear to undergo significant turnover. Tertiary pyrrolizidine alkaloids, if found at all, occur in small amounts in old tissues only. They are derived from the corresponding oxides, and are easily formed spontaneously during alkaloid extraction. The suitability of N-oxides in alkaloid storage is discussed.     

New alkaloids from Aegle marmelos

Four new alkaloids, O-(3,3-dimethylallyl)-halfordinol, N-2-ethoxy-2-(4-methoxyphenyl)ethylcinnamamide, N-2-methoxy-2-[4-(3′,3′-dimethyl