Bioinspired Nucleophilic Attack on a Tungsten-Bound Acetylene: Formation of Cationic Carbyne and Alkenyl Complexes.

Inspired by the proposed inner-sphere mechanism of the tungstoenzyme acetylene hydratase, we have designed tungsten acetylene complexes and investigated their reactivity. Here, we report the first intermolecular nucleophilic attack on a tungsten-bound acetylene (C2H2) in bioinspired complexes employing 6-methylpyridine-2-thiolate ligands. By using PMe3 as a nucleophile, we isolated cationic carbyne and alkenyl complexes.

Diterpenoids and Diacetylenes from the Roots of Aralia cordata with Inhibitory Effects on Nitric Oxide Production.

Bioactivity-guided isolation of a MeOH extract of Aralia cordata led to the isolation of four new ent-pimarane diterpenoids (1-4) and a diacetylene (5) together with 21 known compounds (6-26). Their structures were established based on the interpretation of one- and two-dimensional NMR and HRESIMS data. The absolute configurations of the new isolates were determined by electronic circular dichroism data analysis, single crystal X-ray diffraction, and Mosher's esterification method. All compounds exhibited inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages with IC50 values ranging from 1.1 to 69.4 µM.

Acetylenic fatty acids from Porcelia macrocarpa (Annonaceae) against trypomastigotes of Trypanosoma cruzi: Effect of octadec-9-ynoic acid in plasma membrane electric potential.

Porcelia macrocarpa (Warm.) R. E. Fries (Annonaceae) is an endemic plant in Brazil where its tasty pulp has been eaten fresh. The hexane extract from its flowers was subjected to chromatographic procedures to afford four acetylene derivatives identified as octadec-9-ynoic (stearolic acid - 1), (11E)-octadec-11-en-9-ynoic (santalbic acid - 2), 8-hydroxyoctadec-9,11-diynoic (3) and 8-hydroxyoctadec-17-en-9,11-diynoic (isanolic acid - 4) acids by NMR and HRESIMS. Among tested compounds against trypomastigote forms of T. cruzi, octadec-9-ynoic acid (1) displayed higher potential with IC50 = 27.6 µM and a selectivity index (SI) higher than 7. Compounds 2 and 3 showed IC50 of approximately 60 µM while compound 4 was inactive. The lethal action of the compound 1 was investigated using spectrofluorometric techniques to detect ROS content, plasma membrane permeability and plasma membrane potential by flow cytometry. Compound 1 showed no alteration in the production of ROS of treated trypomastigotes and no alteration of the plasma membrane permeability was observed as detected by the fluorescent probe SYTOX-green after 120 min of incubation. However, by using the potential-sensitive fluorescent probe DiSBAC2(3), compound 1 caused depolarization of the plasma membrane potential when compared to untreated parasites. Our results demonstrated the anti-T. cruzi effects of compounds 1-3 isolated from flowers of P. macrocarpa and indicated that the lethal effect of compound 1 in T. cruzi could be associated to the plasma membrane disturbance of the parasite.

Two new phenolic compounds and antitumor activities of asparinin A from Asparagus officinalis.

Two new phenolic acid compounds, asparoffin C (1) and asparoffin D (2), together with four known compounds, asparenyol (3), gobicusin B (4), 1-methoxy-2-hydroxy-4-[5-(4-hydroxyphenoxy)-3-penten-1-ynyl] phenol (5), and asparinin A (6), have been isolated from the stems of Asparagus officinalis. The structures were established by extensive spectroscopic methods (MS and 1D and 2D NMR). Compound 6 has obvious antitumor activities both in vitro and in vivo.

Biologically Active Acetylenic Amino Alcohol and N-Hydroxylated 1,2,3,4-Tetrahydro-ß-carboline Constituents of the New Zealand Ascidian Pseudodistoma opacum.

The first occurrence of an acetylenic 1-amino-2-alcohol, distaminolyne A (1), isolated from the New Zealand ascidian Pseudodistoma opacum, is reported. The isolation and structure elucidation of 1 and assignment of absolute configuration using the exciton coupled circular dichroism technique are described. In addition, a new N-9 hydroxy analogue (2) of the known P. opacum metabolite 7-bromohomotrypargine is also reported. Antimicrobial screening identified modest activity of 1 toward Escherichia coli, Staphylococcus aureus, and Mycobacterim tuberculosis, while 2 exhibited a moderate antimalarial activity (IC50 3.82 µM) toward a chloroquine-resistant strain (FcB1) of Plasmodium falciparum.

N-Methylniphatyne A, a New 3-Alkylpyridine Alkaloid as an Inhibitor of the Cancer Cells Adapted to Nutrient Starvation, from an Indonesian Marine Sponge of Xestospongia sp.

In the course of searching for selective growth inhibitors of the cancer cells adapted to nutrient starvation, a new 3-alkylpyridine alkaloid named N-methylniphatyne A (1) was isolated from an Indonesian marine sponge of Xestospongia sp. The chemical structure of 1 was determined on the basis of the spectroscopic analysis and comparison with the synthesized 1 and its analogues. Compound 1 showed the cytotoxic activity against PANC-1 cells under the condition of glucose starvation with IC50 value of 16 µM, whereas no growth-inhibition was observed up to 100 µM under the general culture conditions.

Carlina acaulis Exhibits Antioxidant Activity and Counteracts Aß Toxicity in Caenorhabditis elegans.

Carlina acaulis is a medicinal plant that has shown antioxidant activity in in vitro studies, but to date no corresponding in vivo data is available. Therefore, in the present study the antioxidant activity and its impact in counteracting Aß toxicity were studied in the Caenorhabditis elegans model. A dichloromethane extract of the roots of C. acaulis was prepared and characterised via gas-liquid-chromatography/mass-spectrometry (GLC-MS). The in vitro antioxidant activity was confirmed via 2,2-diphenyl-1-picrylhydracyl assay. The extract was further separated by thin layer chromatography into two fractions, one of which was a fraction of the dichloromethane extract of C. acaulis containing mostly Carlina oxide (CarOx). Different strains of C. elegans were employed to study the expression of hsp-16.2p::GFP as a marker for oxidative stress, delocalisation of the transcription factor DAF-16 as a possible mechanism of antioxidant activity, the effect of the drug under lethal oxidative stress, and the effect against beta-amyloid (Aß) toxicity in a paralysis assay. The C. acaulis extract and CarOx showed high antioxidant activity (stress reduction by 47% and 64%, respectively) in C. elegans and could activate the transcription factor DAF-16 which directs the expression of anti-stress genes. In paralysis assay, only the total extract was significantly active, delaying paralysis by 1.6 h. In conclusion, in vivo antioxidant activity was shown for C. acaulis for the first time in the C. elegans model. The active antioxidant compound is Carlina oxide. This activity, however, is not sufficient to counteract Aß toxicity. Other mechanisms and possibly other active compounds are involved in this effect.

Chiral alkynylcarbinols from marine sponges: asymmetric synthesis and biological relevance.

Covering: up to March 2014. Previous review on the topic: B. W. Gung, C. R. Chim., 2009, 12, 489-505. Chiral α-functional lipidic propargylic alcohols extracted from marine sponges, in particular of the pacific genus Petrosia, constitute a class of acetylenic natural products exhibiting remarkable in vitro biological activities, especially anti-tumoral cytotoxicity. These properties, associated to functionalities that are uncommon among natural products, have prompted recent projects on asymmetric total synthesis. On the basis of a three-sector structural typology, three main sub-types of secondary alkynylcarbinols (with either alkyl, alkenyl, or alkynyl as the second substituent) can be identified as the minimal pharmacophoric units. Selected natural products containing these functionalities have been targeted using previously known or on purpose-designed procedures, where the stereo-determining step can be: (i) a C-C bond forming reaction (e.g. the Zn-mediated addition of alkynyl nucleophiles to aldehydes in the presence of chiral aminoalcohols), (ii) a functional layout (e.g. the asymmetric organo- or metallo-catalytic reduction of ynones), or (iii) an enantiomeric resolution (e.g. a lipase-mediated kinetic resolution via acetylation). The promising medicinal importance of these targets is finally surveyed, and future investigation prospects are proposed, such as: (i) further total synthesis of known or future extraction products; (ii) the synthesis of non-natural analogues, with simpler lipophilic environments of the alkynylcarbinol-based pharmacophoric units; (iii) the variation and optimization of both the pharmacophoric units and their lipophilic environment; and (iv) investigations into the biological mode of action of these unique structures.

Synthesis of bioactive speciosins G and P from Hexagonia speciosa.

The first total synthesis of speciosins P and G, previously isolated from Hexagonia speciosa, is reported. These compounds have been synthesized by Sonogashira coupling from readily available starting materials. Siccayne was also synthesized from the same starting material in two steps along with a number of other derivatives. The compounds were tested in the wheat coleoptile bioassay. The most active compound was the intermediate 18, followed by 29 and 17. The structural requirements for activity in these compounds are the presence of methoxy groups in the aromatic ring and a formyl or hydroxy group in the side chain.

Oxirapentyns F-K from the marine-sediment-derived fungus Isaria felina KMM 4639.

Six new highly oxygenated chromene derivatives, oxirapentyns F-K (2-7), one new polyketide (8), one new benzofurane (9), and two known cyclodepsipeptides, isoisariin B and isaridin E, were isolated from the lipophilic extract of the marine-derived fungus Isaria felina KMM 4639. The structures of compounds 2-9 were determined using spectroscopic methods. The relative configurations of compounds 2-7 were established through a combination of NOE data and spin coupling constants, and these results were confirmed by X-ray crystallographic analysis of 4. The absolute structures of all oxirapentyns were assumed based on their biogenetic relationship and confirmed using the modified Mosher's method on 2 and 7. Isariketide (8) showed moderate cytotoxicity toward HL-60 cells.

Sponge-derived acetylenic alcohols, petrosiols, inhibit proliferation and migration of platelet-derived growth factor (PDGF)-induced vascular smooth muscle cells.

Platelet-derived growth factor (PDGF) induces the proliferation and migration of vascular smooth muscle cells (VSMCs), leading to the development of various vascular disorders such as restenosis and atherosclerosis. Therefore, inhibitors of PDGF-induced cellular events would be candidate agents for treating these diseases. During the search for such inhibitors from marine sources, we isolated petrosiols A-D (1-4) and related compounds from the marine sponge Petrosia strongylata. These metabolites, which we previously reported as neurotrophic substances, showed an inhibitory effect on PDGF-induced DNA synthesis at IC50 values of 0.69-2.2 µM. Petrosiol A (1) inhibited PDGF-induced cell proliferation without remarkable cytotoxicity and arrested cell cycle progression from the G0/G1 to S phase by inducing the downregulation of the expression of G1 checkpoint proteins cyclin D1, cyclin E, cyclin-dependent kinases (CDK)2, and CDK4 and the upregulation of the expression of p21 and p27. In addition, petrosiol A (1) inhibited the phosphorylation of PDGF receptor-ß and its downstream proteins such as phospholipase C (PLC)-γ1, Akt, and extracellular signal-regulated kinase (ERK)1/2. These results suggest that 1 inhibited PDGF-induced VSMC proliferation by interrupting the phosphorylation of PDGF receptor-ß followed by downstream signal transduction. Furthermore, petrosiol A (1) suppressed PDGF-induced actin filament dissociation and cell migration, suggesting that 1 and its derivatives may be used for the prevention and treatment of vascular diseases.

Characterization and anti-inflammatory effects of iodinated acetylenic acids isolated from the marine sponges Suberites mammilaris and Suberites japonicus.

The previously unknown compounds 1-4, acetylenic acids with one or two iodine atom(s), were isolated from the marine sponges Suberites mammilaris and Suberites japonicus. Their complete structures were determined using NMR and mass spectrometry. The methylated compounds 1a and 2a exhibited a strong NO inhibitory effect on RAW264.7 cells, while methylated 3a and 4a were inactive in RAW264.7 cells, but highly active in BV2 microglia cells.

Isolation and synthesis of a bioactive benzenoid derivative from the fruiting bodies of Antrodia camphorata.

A new enynyl-benzenoid, antrocamphin O (1,4,7-dimethoxy-5-methyl-6-(3'-methylbut-3-en-1-ynyl)benzo[d][1,3]dioxide), and the known benzenoids antrocamphin A and 7-dimethoxy-5-methyl-1,3-benzodioxole, were isolated from the fruiting bodies of Antrodia camphorata (Taiwanofungus camphoratus). The structure of antrocamphin O was unambiguously assigned by the analysis of spectral data (including 1D and 2D NMR, high-resolution MS, IR, and UV) and total synthesis. Compound 1 was prepared through the Sonogashira reaction of 5-iodo-4,7-dimethoxy-6-methylbenzene and 2-methylbut-1-en-3-yne as the key step. The benzenoids were tested for cytotoxicity against the HT29, HTC15, DLD-1, and COLO 205 colon cancer cell lines, and activities are reported herein.

Acetylenic acid analogues from the edible mushroom Chanterelle (Cantharellus cibarius) and their effects on the gene expression of peroxisome proliferator-activated receptor-gamma target genes.

A new acetylenic acid, (10E,14Z)-9-oxooctadeca-10,14-dien-12-ynoic acid (1), was isolated from the edible mushroom Chanterelle (Cantharellus cibarius), together with a known acetylenic acid, (10E,14Z)-9-hydroxyoctadeca-10,14-dien-12-ynoic acid (2) and their structures were determined through analysis of NMR and mass data. The new acetylenic acid (1) specifically activated peroxisome proliferator-activated receptor (PPAR)-γ with an EC(50) value of 1.88 µM as measured by a reporter gene assay. Expression of PPAR-γ target genes were significantly altered as well, supporting the hypothesis that compound 1 is a PPAR-γ potential agonist that regulates transcription of the PPAR-γ target genes.

Antimicrobial polyacetylenes from Panax ginseng hairy root culture.

Two new polyacetylenes, 1-hydroxydihydropanaxacol (3) and 17-hydroxypanaxacol (4), were isolated from Panax ginseng hairy root culture, along with dihydropanaxacol (1), panaxacol (2) and ginsenoyne D (5). Highly hydroxylated compounds 1-4 were isolated from the medium and compound 5, which was a biosynthetic precursor of compound 1, was isolated from the roots. Compounds 1-4 showed antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Cryptococcus neoformans and Aspergillus fumigatus. It is suggested that P. ginseng plants release antimicrobial polyacetylenes into the surrounding soil from the roots as defense compounds.

Resolution of carboxylic acids using copper(I)-promoted removal of propargylic esters under neutral conditions.

A method for the optical resolution of carboxylic acids is described. Condensation of racemic carboxylic acids with chiral terminal propargyl alcohols gave separable diastereomeric esters. Chromatographic separation followed by heating the individual diastereomers in methanol with catalytic copper(I) halide regenerated the carboxylic acids in good yields and in enantiomeric ratios of ≥94%. This method is particularly useful for the resolution of carboxylic acids that are incompatible with conventional ester hydrolysis.

Carlina oxide--a natural polyacetylene from Carlina acaulis (Asteraceae) with potent antitrypanosomal and antimicrobial properties.

Carlina acaulis (Asteraceae) has a long history of medicinal use in Europe due to its antimicrobial properties. The strong activity of Carlina oxide, themain compound of the essential oil of C. acaulis against two MRSA strains, Streptococcus pyogenes, Pseudomonas aeruginosa, Candida albicans, and C. glabrata was confirmed. A strong and selective activity against Trypanosoma brucei brucei with an IC50 of 1.0 µg/mL and a SI of 446 compared to human HeLa cells was recorded. The selective toxicity of Carlina oxide makes it a promising lead compound for the development of drugs to treat African trypanosomiasis and multiresistant gram-positive bacteria.

Acetylenic sesquiterpenoids from cultures of the basidiomycete Stereum cf. hirsutum BCC 26597.

A new acetylenic sesquiterpenoid, stereyne A (1), and its acetonide derivative, stereyne B (2), were isolated from cultures of the basidiomycete Stereum cf. hirsutum BCC 26597. The structures were elucidated by spectroscopic analysis and a chemical correlation. Their absolute configurations were determined by application of the modified Mosher's method. They represent new structural type of sesquiterpenoids from Stereum.

Search for antifungal compounds from the wood of durable tropical trees.

Research on antifungal compounds from the durable wood from French Guiana Amazonian forest trees highlights the correlation between the activity of their extracts against wood-rotting fungi and human pathogens. The fractionation of an ethyl acetate extract of Sextonia rubra wood led to the isolation of rubrenolide (1) and rubrynolide (2). The potential of compounds 1 and 2 is described through the evaluation of their activity against 16 pathogenic fungi and their cytotoxicity toward NIH-3T3 mammalian fibroblast cells.

Polyacetylenes and flavonoids from the aerial parts of Bidens pilosa.

Bidens pilosa is used in various folk medicines such as antimalarial, antibacterial, blood pressure-lowering, and antihyperglycemic agents. Phytochemical investigation of the aerial parts of this plant yielded 10 polyacetylenes and 9 flavonoids, including four new polyacetylenes (5, 7- 9) and one new chalcone glucoside (11). The molecular structures of the isolated compounds were elucidated by comprehensive spectroscopic analysis.