Neopetrosiamine A,biologically active bis-piperidine alkaloid from the Caribbean sea sponge Neopetrosia proxima

A new tetracyclic bis-piperidine alkaloid, neopetrosiamine A (1), has been extracted from the marine sponge Neopetrosia proxima collected off the west coast of Puerto Rico. The structure of compound 1 was elucidated by analysis of spectroscopic data coupled with careful comparisons of its ¹H and ¹³C NMR data with those of a well-known 3-alkylbis-piperidine alkaloid model. The new alkaloid displayed strong in vitro cytotoxic activity against a panel of cancer cell lines as well as in vitro inhibitory activity against the pathogenic microbes Mycobacterium tuberculosis and Plasmodium falciparum.     

A benzopyrroloisoquinoline alkaloid from Ficus fistulosa

A new benzopyrroloisoquinoline alkaloid, fistulosine (1), was isolated from the stem-bark of Ficus fistulosa (Moraceae) collected in Singapore, along with three known phenanthroindolizidine alkaloids, (?)-13aα-antofine (2), (?)-14β-hydroxyantofine (3) and (?)-13aα-secoantofine (4). (?)-13aα-Antofine (2) accounted for the antifungal activity against Aspergillus fumigatus and Candida albicans originally observed in the crude alkaloid extract.     

Serratezomines D and E,new Lycopodium alkaloids from Lycopodium serratum var. serratum

Two new Lycopodium alkaloids, serratezomines D (1) and E (2), were isolated from the club moss Lycopodium serratum var. serratum. Serratezomine D (1) is a new lucidine-type alkaloid, while serratezomine E (2) is a new phlegmarane-type alkaloid. The structures and relative stereochemistry of 1 and 2 were elucidated on the basis of spectroscopic data. Serratezomine D (1) exhibited an inhibitory activity against acetylcholinesterase.     

Antiplasmodial alkaloids from bulbs of Amaryllis belladonna Steud.

A bioassay-guided fractionation and chemical investigation of Amaryllis belladonna Steud. bulbs resulted in the isolation and identification of the new crinane alkaloid 1,4-dihydroxy-3-methoxy powellan (1), along with the 3 known crinane alkaloids 2–4 and the two lycorane alkaloids 5–6. The structures were elucidated by interpretation of combined HR-ESIMS, CD and 2D NMR spectroscopic data. Among these isolated compounds the lycorane-type alkaloid acetylcaranine (5) exhibited strong antiplasmodial activity, while compounds 3 and 4 were moderately active, and compounds 1 and 6 were inactive.     

A new pyrrolizidine alkaloid and other constituents from the roots of Ligularia achyrotricha (Diels) Ling

Ligularia achyrotricha (Diels) Ling has been used as a traditional Tibetan herbal medicine. Ligulachyroine A (1), a new twelve-membered macrocyclic pyrrolizidine alkaloid with a ketonic group located at C-3 and an hydroxy group linked at C-8, was isolated from the roots of L. achyrotricha. It is particularly noteworthy that the structure of 1 rarely appears in any other naturally occurring twelve-membered macrocyclic pyrrolizidine alkaloid reported to date. Three known lignans (2–4) and eight known coniferyl and sinapyl alcohol derivatives (5–12) were also obtained in this species. Their structures were elucidated through a careful analysis of their IR, MS, and NMR spectra. Compound 1 exhibited moderate activity against HL-60 and SMMC-7721 cells.     

Five new alkaloids from Aconitum apetalum (Ranunculaceae)

Twenty-one alkaloids, including five new ones, acoapetaldines A–E (1–5), were isolated from the whole plants of Aconitum apetalum. Among them, 1 is an aconitine-type diterpenoid alkaloid, 2 and 3 are aporphine alkaloids and 4 and 5 are napelline-type diterpenoid alkaloids. The structures of the new alkaloids were elucidated by spectroscopic data analysis and that of acoapetaldine D (4) was confirmed by single crystal X-ray crystallography. Acoapetaldine A (1) and aconorine (12) exhibited moderate anti-tobacco mosaic virus (anti-TMV) activity, while corydine (15) displayed moderate antimicrobial activity against Pseudomonas aeruginosa.     

Bisleuconothine A,an eburnane–aspidosperma bisindole alkaloid from Leuconotis griffithii

A new bisindole alkaloid, bisleuconothine A (1) consisting of an eburnane–aspidosperma type skeleton, was isolated from the bark of Leuconotis griffithii. The structure including absolute stereochemistry was elucidated on the basis of 2D NMR data and X-ray analysis. Bisleuconothine A (1) showed cell growth inhibitory activity against various human cancer cell lines.     

Ceratinadins A–C,new bromotyrosine alkaloids from an Okinawan marine sponge Pseudoceratina sp.

Three new bromotyrosine alkaloids, ceratinadins A–C (1–3), were isolated from an Okinawan marine sponge Pseudoceratina sp. and the structures of 1–3 were elucidated on the basis of spectroscopic data. Ceratinadin A (1) was a novel bromotyrosine alkaloid possessing an N-imidazolyl-quinolinone moiety. Ceratinadins A (1) and B (2) showed antifungal activity.     

Alstiphyllanines E–H,picraline and ajmaline-type alkaloids from Alstonia macrophylla inhibiting sodium glucose cotransporter

Three new picraline-type alkaloids, alstiphyllanines E–G (1–3) and a new ajmaline-type alkaloid, alstiphyllanine H (4) were isolated from the leaves of Alstonia macrophylla together with 16 related alkaloids (5–20). Structures and stereochemistry of 1–4 were fully elucidated and characterized by 2D NMR analysis. Alstiphyllanines E and F (1 and 2) showed moderate Na⁺-glucose cotransporter (SGLT1 and SGLT2) inhibitory activity. A series of a hydroxy substituted derivatives 21–28 at C-17 of the picraline-type alkaloids have been derived as having potent SGLT inhibitory activity. 10-Methoxy-N(1)-methylburnamine-17-O-veratrate (6) exhibited potent inhibitory activity, suggesting that the presence of an ester side chain at C-17 may be important to show SGLT inhibitory activity. Structure activity relationship of alstiphyllanines on inhibitory activity of SGLT was discussed.     

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.     

A bromopyrrole-containing diterpene alkaloid from the Okinawan marine sponge Agelas nakamurai activates the insulin pathway in Huh-7 human hepatoma cells by inhibiting protein tyrosine phosphatase 1B

Agelasine G (1), a known bromine-containing diterpene alkaloid, was isolated as a new type of protein tyrosine phosphatase (PTP) 1B inhibitor together with ageline B (2), an inactive debromo-derivative of 1, from the marine sponge Agelas nakamurai collected at Iriomote Island in Okinawa, Japan. Further biological evaluations revealed that compound 1 exhibited selective inhibitory activity against PTP1B over T-cell PTP and CD45 phosphatase. Compound 1 also enhanced the insulin-stimulated phosphorylation levels of Akt in Huh-7 cells more strongly than compound 2. The results obtained in this study suggest that compound 1 activates the insulin signaling pathway by inhibiting PTP1B activity.     

Death receptor 5 targeting activity-guided isolation of isoflavones from Millettia brandisiana and Ardisia colorata and evaluation of ability to induce TRAIL-mediated apoptosis

Death receptor 5 (DR5) is an apoptosis-inducing membrane receptor for TNF-related apoptosis-inducing ligand (TRAIL). On screening for compounds that enhance DR5 expression using a luciferase assay with DLD-1/SacI, we previously identified 4′-demethyltoxicarol isoflavone (1) isolated from the leaves of Millettia brandisiana. In this study, we revealed that 1 sensitized TRAIL-resistant human gastric adenocarcinoma (AGS) cells to TRAIL-induced apoptosis by up-regulating the expression of DR5. 1 induced DR5 expression at both the mRNA and protein level. A human recombinant DR5/Fc chimera remarkably inhibited 1-induced apoptosis. These results suggest that the enhancement of DR5 expression by 1 was critical to the cell death. Furthermore, a MeOH extract of the bark of Ardisia colorata markedly enhanced DR5 activity in this screening system. Bioassay-guided fractionation of A. colorata led to the isolation and identification of a new isoflavone, coloratanin A (3), together with ten known compounds. The chemical structure of the new compound was elucidated on the basis of a spectroscopic analysis.     

Two new alkaloids from Pachysandra terminalis and their antibacterial activity assessment

Phytochemical investigation of a 90 % ethanol extract of Pachysandra terminalis Sieb. Et Zucc led to the isolation of a novel alkaloid, terminamine T (1); a new pregnane-type alkaloid, terminamine U (2); and four known pregnane-type alkaloids (3-6). The structures of these compounds were elucidated on the basis of nuclear magnetic resonance spectra, mass spectrometry data, single-crystal X-ray diffraction, and by a comparison with data from the literature. All compounds were evaluated for their antibacterial activities against gram-positive (S. aureus, ATCC 29213) and gram-negative (E. coli, ATCC 25922) bacteria. Compounds 2-6 exhibited generally modest to poor antibiotic properties. Furthermore, compound 2 showed antibacterial activity against methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-resistant Staphylococcus aureus (MRSA), and methicillin-resistant Staphylococcus aureus USA300 (LAC) with a minimal inhibitory concentration (MIC) value of 32 μg/mL (75 μM) and minimum bactericidal concentration (MBC) values of 64, 128, and 128 μg/mL (150, 300, and 300 μM), respectively.     

Monoterpenoid indole alkaloids from Palicourea crocea

A new monoterpenoid indole alkaloid N-oxide, 3,4-dihydro-1-(1-β-d-glucopyranosyloxy-1,4a,5,7a-tetrahydro-4-methoxycarbonylcyclopenta[c]pyran-7-yl)-β-carboline-N²-oxide (3) and two known monoterpenoid indole alkaloids, croceaine A (1) and psychollatine (2), were isolated from Palicourea crocea (Rubiaceae) from Trinidad. The structures of 1–3 were determined on the basis of spectral and other physical data. Compounds 1 and 2 were previously isolated from plants of different genera viz. Palicourea crocea and Psychotria umbellata, respectively, both collected in Brazil. The results support the proposal that the genus Palicourea and the subgenus Heteropsychotria should be combined into a single genus.     

Omphalocarpoidone,a new lanostane-type furano-spiro-γ-lactone from the wood of Tridesmostemon omphalocarpoides Engl. (Sapotaceae)

Phytochemical studies of the wood and the stem bark of Tridesmostemon omphalocarpoides Engl. (Sapotaceae) led to the isolation of omphalocarpoidone (1), a new lanostane-type furano-spiro-γ-lactone together with β-amyrin acetate (2), taraxerol (3), spinasterol (4), lichexanthone (5), epi-catechin (6), spinasterol 3-O-β-d-glucopyranoside (7), tormentic acid (8), and 1,2,3,4-tetrahydronorharman-1-one (9). Their structures were established on the basis of extensive NMR studies, mass spectrometry, and by comparison of the data with those previously reported in the literature. The structure of the new secondary metabolite was later confirmed by X-ray crystallography. Except for spinasterol, the antimicrobial activities of these secondary metabolites were investigated on ten bacterial strains and the alkaloid 9 showed a significant activity against Escherichia coli with a MIC at 16 μg/mL.     

Alkaloids of Toddalia asiatica (Rutaceae)

Phytochemical investigation of the alkaloidal extract of the roots of Toddalia asiatica led to the isolation of a new seco-benzophenanthridine alkaloid (1) and twelve known alkaloids (2–13). The new structure was elucidated by means of spectroscopic analysis, and the known alkaloids were identified by comparison with the literature. Among these alkaloids, 1 and 5–7 were reported from the genus Toddalia for the first time. The distribution of the isolated alkaloids at genus/family level was presented via network analysis and their chemotaxonomic significance was also discussed.     

Glycopentaphyllone: The first isolation of hydroperoxyquinolone from the fruits of Glycosmis pentaphylla

A new hydroperoxyquinolone alkaloid, glycopentaphyllone (1), along with nine compounds (2–10), was isolated from the fruits of Glycosmis pentaphylla. Their structures were elucidated on the basis of spectroscopic methods. The absolute configuration of glycopentaphyllone at C-2′ was established as S-configuration by applying Mosher's method. In addition, the completed assignments of ¹³C NMR as well as 2D NMR spectral data of compound 5 were reported herein for the first time. Also, all isolates were evaluated for antibacterial activity against Escherichia coli TISTR 780, Salmonella typhimurium TISTR 292, Staphylococcus aureus TISTR 1466, and Methicillin-resistant S. aureus SK1.     

Enhancing activity of antibiotics against Staphylococcus aureus: Zanthoxylum capense constituents and derivatives

Six compounds (1–6), isolated from the methanol extract of the roots of the African medicinal plant Zanthoxylum capense Thunb. (Rutaceae), and seven ester derivatives (7–13) were evaluated for their antibacterial activities and modulatory effects on the MIC of antibiotics (erythromycin, oxacillin, and tetracycline) and ethidium bromide (EtBr) against a Staphylococcus aureus reference strain (ATCC 6538). Using the same model, compounds 1–13 were also assessed for their potential as efflux pump inhibitors by a fluorometric assay that measures the accumulation of the broad range efflux pump substrate EtBr. Compounds 8 and 11 were further evaluated for their antibacterial, modulatory and EtBr accumulation effects against four additional S. aureus strains, which included two clinical methicillin-resistant S. aureus (MRSA) strains. Compounds (1–13) have not shown antibacterial activity at the concentration ranges tested. When evaluated against S. aureus ATCC 6538, oxychelerythrine (1) a benzophenanthridine alkaloid, showed the highest modulatory activity enhancing the susceptibility of this strain to all the tested antibiotics from two to four-fold. Ailanthoidiol diacetate (8) and ailanthoidiol di-2-ethylbutanoate (11) were also good modulators when combined with EtBr, increasing the bacteria susceptibility by four and two-fold, respectively. In the EtBr accumulation assay, using ATCC 6538 strain, the phenylpropanoid (+)-ailanthoidiol (6) and most of its ester derivatives (8−11) exhibited higher activity than the positive control verapamil. The highest effects were found for compounds 8 and 11 that also increased the accumulation of EtBr, using S. aureus ATCC 25923 as model. Furthermore, both compounds (8, 11) were able to enhance the ciprofloxacin activity against the MRSA clinical strains tested, causing a reduction of the antibiotic MIC values from two to four-fold. The EtBr accumulation assay revealed that this modulation activity was not due to an inhibition of efflux pumps mechanism.These results suggested that Z. capense constituents may be valuable as leads for restoring antibiotic activity against MRSA strains.     

Synthesis and biological activities of novel pyrazolomatrine derivatives

In continuation of our program aimed at the development of new natural product-based pesticides, a series of novel pyrazolomatrine derivatives were prepared by structural modifications of matrine, isolated as a quinolizidine alkaloid from the roots of Sophora flave. Their structures were confirmed by ¹H NMR, HRMS, etc. Moreover, the steric structures of three compounds were determined by single-crystal X-ray diffraction. Among all derivatives, 19-(naphthyl-2-oyl)pyrazolomatrine (5y) showed 3.13-fold more potent acaricidal activity than its precusor matrine against Tetranychus cinnabarinus; 19-(4-methylbenzoyl)pyrazolomatrine (5j) and 19-(3,5-dimethylbenzoyl)pyrazolomatrine (5k) displayed the promising aphicidal activity against Aphis citricola van der. Their structure-activity relationships were also observed.     

Pochonicine,a polyhydroxylated pyrrolizidine alkaloid from fungus Pochonia suchlasporia var. suchlasporia TAMA 87 as a potent β-N-acetylglucosaminidase inhibitor

A new polyhydroxylated pyrrolizidine alkaloid designated as pochonicine (1) was isolated from a solid fermentation culture of the fungal strain Pochonia suchlasporia var. suchlasporia TAMA 87. The structure of 1 was determined using NMR and MS techniques as (1R*, 3S*, 5S*, 6S*, 7R*, 7a S*)-5-acetamidomethyl-3-hydroxymethyl-1,6,7-trihydroxypyrrolizidine. Pochonicine (1) showed potent inhibition against β-N-acetylglucosaminidases (GlcNAcases) of various organisms including insects, fungi, mammals, and a plant but no inhibition against β-glucosidase of almond, α-glucosidase of yeast, or chitinase of Bacillus sp. The GlcNAcase inhibitory activity of pochonicine (1) was comparable to nagstatin, a potent GlcNAcase inhibitor of natural origin.