Differential Sequestration of a Cytotoxic Vismione from the Host Plant Vismia baccifera by Periphoba arcaei and Pyrrhopyge thericles.

We sought to compare the abilities of the specialist Lepidoptera Pyrrhopyge thericles (Hesperiidae) and the generalist Periphoba arcaei (Saturniidae) to assimilate three highly cytotoxic compounds from their larval host plant, Vismia baccifera (Clusiaceae) and to determine whether either insect discriminated in its assimilation of the compounds that are structurally similar but of variable cytotoxicity. Vismione B (1), deacetylvismione A (2), and deacetylvismione H (3) are cytotoxic compounds isolated from V. baccifera. Compound 1 was found in the 2nd and 3rd instars of P. arcaei, but not in the mature larvae or the pupae. Pyrrhopyge thericles assimilated trace quantities of compound 1 and deacetylvismione A (2), which were both found in the 3rd and 4th instars. In extracts of V. baccifera, compound 2 is present at levels approximately 6-fold greater than compound 1, indicating that the generalist P. arcaei is capable of selectively sequestering cytotoxic compounds from its host plant. Compounds 1 and 2 show comparable cytotoxicities in three different cancer cell lines, suggesting that properties other than cytotoxicity are responsible for the selective sequestration of 1 by P. arcaei. This study represents the first time that sequestration of this class of compounds has been recorded in the Lepidoptera.

Our oceans, ourselvesThe Blue Machine: How the Ocean Works Helen Czerski Norton, 2023. 464 pp.

An oceanographer's expansive portrait of the marine world captures its vitality and complexity.

Significant natural product biosynthetic potential of actinorhizal symbionts of the genus frankia, as revealed by comparative genomic and proteomic analyses.

Bacteria of the genus Frankia are mycelium-forming actinomycetes that are found as nitrogen-fixing facultative symbionts of actinorhizal plants. Although soil-dwelling actinomycetes are well-known producers of bioactive compounds, the genus Frankia has largely gone uninvestigated for this potential. Bioinformatic analysis of the genome sequences of Frankia strains ACN14a, CcI3, and EAN1pec revealed an unexpected number of secondary metabolic biosynthesis gene clusters. Our analysis led to the identification of at least 65 biosynthetic gene clusters, the vast majority of which appear to be unique and for which products have not been observed or characterized. More than 25 secondary metabolite structures or structure fragments were predicted, and these are expected to include cyclic peptides, siderophores, pigments, signaling molecules, and specialized lipids. Outside the hopanoid gene locus, no cluster could be convincingly demonstrated to be responsible for the few secondary metabolites previously isolated from other Frankia strains. Few clusters were shared among the three species, demonstrating species-specific biosynthetic diversity. Proteomic analysis of Frankia sp. strains CcI3 and EAN1pec showed that significant and diverse secondary metabolic activity was expressed in laboratory cultures. In addition, several prominent signals in the mass range of peptide natural products were observed in Frankia sp. CcI3 by intact-cell matrix-assisted laser desorption-ionization mass spectrometry (MALDI-MS). This work supports the value of bioinformatic investigation in natural products biosynthesis using genomic information and presents a clear roadmap for natural products discovery in the Frankia genus.

Malyngolide dimer, a bioactive symmetric cyclodepside from the panamanian marine cyanobacterium Lyngbya majuscula.

Fractionation of the extract of the marine cyanobacterium Lyngbya majuscula collected from Panama led to the isolation of malyngolide dimer (1). The planar structure of 1 was determined using 1D and 2D NMR spectroscopy and HRESI-TOFMS. The absolute configuration was established by chemical degradation followed by chiral GC-MS analyses and comparisons with an authentic sample of malyngolide seco-acid (4). Compound 1 showed moderate in vitro antimalarial activity against chloroquine-resistant Plasmodium falciparum (W2) (IC(50) = 19 microM) but roughly equivalent toxicity against H-460 human lung cell lines. Furthermore, because the closely related cyanobacterial natural product tanikolide dimer (5) was a potent SIRT2 inhibitor, compound 1 was evaluated in this assay but found to be essentially inactive.

Antitrypanosomal activity of a novel norlignan purified from Nectandra lineata.

Bioactivity-guided fractionation of a MeOH-EtOAc extract from the young leaves of Nectandra lineata (Lauraceae), using a Trypanosoma cruzi bioassay resulted in the isolation of a novel norlignan 3'-methoxy-3,4-methylenedioxy-4',7-epoxy-9-nor-8,5'-neolignan-9'-acetoxy (1), together with the known compound, 3'-methoxy-3,4-methylenedioxy-4'-7-epoxy-9-nor-8,5'-neolignan-7,8'-diene (2). Compounds 1 and 2 were shown to inhibit the growth of T. cruzi epimastigotes in axenic culture.

Bielschowskysin, a gorgonian-derived biologically active diterpene with an unprecedented carbon skeleton.

Bielschowskysin is a naturally occurring diterpene isolated from the Caribbean gorgonian octocoral Pseudopterogorgia kallos. Its highly oxygenated hexacyclic structure is based on a previously undescribed tricyclo[9.3.0.0(2,10)]tetradecane ring system that was established through spectroscopic analysis and X-ray crystallographic analysis. Bielschowskysin was shown to exhibit antimalarial activity against Plasmodium falciparum as well as strong anticancer activity against two human cancer cell lines.

A novel DNA-based microfluorimetric method to evaluate antimalarial drug activity.

This paper describes the development of a novel microfluorimetric assay to measure the inhibition of Plasmodium falciparum based on the detection of parasitic DNA by intercalation with PicoGreen. The method was used to determine parasite inhibition profiles and 50% inhibitory concentration values of known or potential antimalarial drugs. Values for parasite inhibition with known anti-malarial drugs using the PicoGreen assay were comparable with those determined by the standard method based upon the uptake of 3H-hypoxanthine and the Giemsa stain microscopic technique. The PicoGreen assay is rapid, sensitive, reproducible, easily interpreted, and ideally suited for screening of large numbers of samples for anti-malarial drug development.

Hydrosoluble formazan XTT: its application to natural products drug discovery for Leishmania.

A colorimetric method for measuring the viability of Leishmania promastigotes is described that is based on the reduction of the tetrazolium salt, XTT, to a water-soluble formazan. Values obtained by the XTT method correlated well with parasite number (r=0.965) and with methods that rely upon the reduction of MTT or MTS (r=0.96 and 0.97, respectively). The IC(50) values obtained by XTT method with amphotericin-B, miltefosine and ketoconazole were similar to those previously reported by other methods. The XTT method proved to be a reliable and convenient method for the screening of methanolic extracts from 1059 plants and was used for the bioassay-guided fractionation of the alkaloid aegeline from Sarcorhachis naranjoana.

Ecology- and bioassay-guided drug discovery for treatments of tropical parasitic disease: 5alpha,8alpha-epidioxycholest-6-en-3beta-ol isolated from the mollusk Dolabrifera dolabrifera shows significant activity against Leishmania donovani.

An ecology- and bioassay-guided search employed to discover compounds with activity against tropical parasitic diseases and cancer from the opisthobranch mollusk, Dolabrifera dolabrifera, led to the discovery of antileishmanial properties in the known compound, 5alpha,8alpha-epidioxycholest-6-en-3beta-ol (1). Compound 1 was identified through nuclear magnetic resonance spectroscopy (1H, 13C) and mass spectrometry. The compound was concentrated in the digestive gland of D. dolabrifera, but was not detected in other body parts, fecal matter or mucus. Compound 1 showed an IC50 of 4.9 microM towards the amastigote form of Leishmania donovani compared with an IC50 of 281 microM towards the control Vero cell line, a 57.3-fold difference, and demonstrated no measurable activity against Plasmodium falciparum, Trypanosoma cruzi, and the breast cancer cell line, MCF-7.

Antimalarial linear lipopeptides from a Panamanian strain of the marine cyanobacterium Lyngbya majuscula.

As part of the Panama International Cooperative Biodiversity Groups (ICBG) project, two new (2, 4) and two known (1, 3) linear alkynoic lipopeptides have been isolated from a Panamanian strain of the marine cyanobacterium Lyngbya majuscula. Carmabin A (1), dragomabin (2), and dragonamide A (3) showed good antimalarial activity (IC50 4.3, 6.0, and 7.7 microM, respectively), whereas the nonaromatic analogue, dragonamide B (4), was inactive. The planar structures of all four compounds were determined by NMR spectroscopy in combination with mass spectrometry, and their stereoconfigurations were established by chiral HPLC and by comparison of their optical rotations and NMR data with literature values.

Antiplasmodial metabolites isolated from the marine octocoral Muricea austera.

Bioassay-guided fractionation of the MeOH extract from the octocoral Muricea austera collected in the Pacific coast of Panama led to the isolation of eight compounds, including three tyramine derivatives (1-3), two steroidal pregnane glycosides (4, 5), and three sesquiterpenoids (6-8). Compounds 2-5 are new natural products, and their structures were determined on the basis of their spectroscopic data (HRMS, 1D and 2D NMR, and CD studies). The antiprotozoal activities of the natural compounds 1-8 as well as those of a series of synthetic glycosides (11-22) and tyramine derivatives (23-35) were evaluated in vitro against a drug-resistant Plasmodium falciparum and intracellular form of Trypanosoma cruzi.

Weakly antimalarial flavonol arabinofuranosides from Calycolpus warszewiczianus.

Three new flavonol arabinosides (2-4) were isolated from the young leaves of Calycolpus warszewiczianus. The structures were determined as myricetin-3-O-alpha-L-3' '-acetylarabinofuranoside (2), myricetin-3-O-alpha-L-3' ',5' '-diacetylarabinofuranoside (3), and 5-galloylquercetin-3-O-alpha-L-arabinofuranoside (4). Molecular structures were elucidated using NMR spectroscopy in combination with IR and MS data. Two known compounds, myricetin-3-O-alpha-L-arabinofuranoside (1) and (-)-epi-catechin (5), were also isolated. The compounds were tested in vitro against a chloroquine-resistant strain of Plasmodium falciparum, Leishmania mexicana, and Trypanosoma cruzi parasites. Compound 4 demonstrated weak activity against a chloroquine-resistant strain of P. falciparum (14.5 microM), whereas none of the compounds demonstrated activity against L. mexicana and T. cruzi at the concentrations of 40 and 50 microg/mL, respectively, and no cytotoxicity was detected against mammalian cells below 100 microg/mL.

Caucanolides A-F, unusual antiplasmodial constituents from a colombian collection of the gorgonian coral Pseudopterogorgia bipinnata.

Six new diterpenoids, caucanolides A-F (1-6), have been isolated from extracts of the gorgonian octocoral Pseudopterogorgia bipinnata collected near the Colombian Southwestern Caribbean Sea. The structures of 1-6 were elucidated by comprehensive analysis of spectroscopic data. The caucanolides showed in vitro antiplasmodial activity against the malaria parasite, Plasmodium falciparum. In addition to possessing structures based on novel carbon skeletons, one of these metabolites, caucanolide B (2), constitutes the only example from nature of a secondary metabolite possessing the N(1),N(1)-dimethyl-N(2)-acylformamidine functionality.

Leptolide, a new furanocembranolide diterpene from Leptogorgia alba.

Six furanocembranolides (1-6) and one pseudopterolide (7) have been isolated from the octocorals Leptogorgia alba and Leptogorgia rigida, collected on the Pacific coast of Panama. Compound 1, named leptolide, has a new structure closely related to the neurotoxin lophotoxin (3). The X-ray structures of 1-3 were determined, and the absolute configurations of 2-7 are discussed. Compounds 1-7 were evaluated in vitro against drug-resistant Plasmodium falciparum.

Briarellins J-P and polyanthellin A: new eunicellin-based diterpenes from the gorgonian coral Briareum polyanthes and their antimalarial activity.

A new chemical study of the hexane extract of the gorgonian Briareum polyanthes collected in Puerto Rico afforded 10 new diterpenes of the eunicellin class, briarellins 1-9 and polyanthellin A (10), along with the known diterpene briarellin D (11). The structures and relative stereochemistry of metabolites 1-10 were assigned on the basis of NMR studies, chemical methods, and comparisons to the spectral properties of 11. A reassessment of prior structural assignment for briarellin A and two known sclerophytin-type diterpenes, 13 and 14, is proposed. Antimalarial tests on 1-6 and 8-12 indicated that they were active against Plasmodium falciparum.

Five new cassane diterpenes from Myrospermum frutescens with activity against Trypanosoma cruzi.

Five novel cassane diterpenes (1-5) with activity against Trypanosoma cruzi were isolated from leaves of Myrospermum frutescens. The structures were determined as 18-hydroxycassan-13,15-diene (1), 6beta,18-dihydroxycassan-13,15-diene (2), 6beta-hydroxy-18-acetoxycassan-13,15-diene (3), 18-acetoxy-13,15-diene-19-cassanoic acid (4), and 6beta,13beta-dihydroxy-18-acetoxycassan-14(17),15-diene (5). Structures were elucidated by spectroscopic analysis (NMR and HRCIMS) and by the synthesis of derivatives 2a and 2b. Compounds 3 and 5 were more active against the extracellular form of the parasite (11 and 16 microM, respectively) than the intracellular forms, while compounds 1 and 2 were more active against the more clinically relevant intracellular forms of the parasite (17 microM). Compounds 1 and 2 were approximately 9-fold more toxic toward T. cruzi than toward human fibroblasts, the cell type that serves as the parasite's mammalian host cell.

Aporphine alkaloids from Guatteria spp. with leishmanicidal activity.

Fractionation of Guatteria amplifolia yielded the alkaloids xylopine (1), nornuciferine (4), lysicamine (6), and laudanosine (5). Fractionation of Guatteria dumetorum yielded the alkaloids cryptodorine (2) and nornantenine (3). Compounds 1-4 demonstrated significant activity against Leishmania mexicana and L. panamensis. Xylopine (1) was among the most active compounds (LD 50 = 3 microM) and showed a 37-fold higher toxicity towards L. mexicana than macrophages, the regular host cells of Leishmania spp.

Novel cassane and cleistanthane diterpenes from Myrospermum frutescens: absolute stereochemistry of the cassane diterpene series.

Four new diterpenes (1-4) were isolated from the leaves of Myrospermum frutescens as minor constituents. Chagresnol (1), 6beta,18-diacetoxycassan-13,15-diene (2), and chagreslactone (3) possess cassane skeletons, while chagresnone (4) exhibits a cleistanthane skeleton. Molecular structures and their relative stereochemistries were elucidated using NMR spectroscopy in combination with UV, IR, and MS spectral data. Although compound 2 was previously reported as a synthetic product, we report its first isolation as a natural product. Derivative products (10-13) were obtained to test their activities against Chagas's disease. In addition, the absolute stereochemistry of the previously isolated cassane diterpene 5 from M. frutescens is presented.

New cytotoxic naphthopyrane derivatives from Adenaria floribunda.

Bioassay-guided fractionation of an EtOAc/MeOH extract of Adenaria floribunda young leaves using MCF-7, H-460, and SF-268 cancer cell lines yielded four new active compounds named adenaflorins A-D (1-4). Their chemical structures were determined by spectroscopic means. Adenaflorin A (1) was the most cytotoxic.

Bioactive constituents from three Vismia species.

Bioassay-guided fractionation of the methanolic extracts of Vismia baccifera, V. jefensis, and V. macrophylla against human breast, CNS, and lung cancer cell lines resulted in the isolation of a new compound, ferruginin C (1), and seven known compounds, ferruginins A (2) and B (3), vismin (4), harunganin (5), vismione B (6), deacetylvismione H (7), and deacetylvismione A (8), as active constituents. In addition, bivismiaquinone (9) and vismiaquinone (10) were obtained as inactive constituents. The structure of ferruginin C was elucidated by spectroscopic means. Compounds 6-8 were the most active, and the cytotoxic activity of compounds 2-5 and 7 is reported for the first time.