Quite a number of methods of extraction and separation are currently used to isolate and purify secondary metabolites from complex mixtures, but "green" technologies are still far from being used routinely in public research laboratories. In recent years, supercritical fluid extraction (SFE) and chromatography (SFC) have gained increasing interest in production of high-value plant extracts for pharmaceutical, cosmetic and food industries. SFC enables fast and reliable separation of biomolecules from complex mixtures [1,2]. Supercritical carbon dioxide (SC-CO2) is an eco-friendly, chemically inert, nontoxic and noninflammable fluid. As a green material, SC-CO2 has low viscosity and high diffusivity that make it suitable as a solvent for SFE and as a mobile phase for SFC. Previous chemical investigation of Stillingia lineata ((Lam.) Müll. Arg. Euphorbiaceae) leaves led to the isolation of the rare C20-flexibilane tonantzitlolones (TZLs) (PKC activators and potent anti-tumor agents) [3] and tigliane derivatives (strong inhibitors of Chikungunya viral replication) [4 – 6]. This plant was selected to validate our green approach aiming to specifically extract, then isolate diterpenoids of interest. According to a pre-determined experimental plan, sequential SFE-CO2 was carried out by varying pressure, temperature, flow rate and step duration. For each experiment, an ethanol step gradient was performed, affording six fractions (Figure below). Identification of compounds was achieved by LC-UV-HRMS [2], then compared with standards and classified into different chemical classes (TZLs, diterpenes, chlorophylls and glycosylated flavonoids). Their relative proportions were subsequently determined by measurement of UV peak areas, allowing selecting optimal SFE conditions, and diterpene-enriched fraction for further SFC purifications. This approach not only has the benefit of using eco-friendly methodologies, but it also allows a concurrent prefractionation during the extraction step.

Iridoid glycosides, which form a large group of cyclopentane monoterpenoids, are biosynthesized by a large number of plant species belonging to approximately 20 important botanical families. They possess a highly functionalized aglycon, which may be regarded as starting material for the synthesis of a number of new chiral molecules. For this study, approximately 500 species were selected from iridoid-containing families. A methodology, based on the combination of different analytical and spectroscopic techniques such as LC/UV/DEDL, LC/MS and NMR, was developed in order to select plants of interest. Among these, we found that the New Caledonian species Oxera coronata (Lamiaceae) produced high level of 8-O-acetylharpagide (AH) in leaves, twigs and fruits. We will present the methodology used to detect and isolate iridoids, the quantitative evaluation of AH in O. coronata, and its potential uses as raw material for semi-synthesis.

Malaria still remains an important parasitic disease in developing countries. For example, new cases of resistance appear in South America, particularly in French Guiana [1]. A systematic biological evaluation on Plasmodium falciparum of plant extracts collected in this country has allowed to select two Clusiaceae species, Moronobea coccinea Aubl. and Symphonia sp. This family is known to be a rich source of polycyclic polyprenylated acylphloroglucinols (PPAPs) with a large spectre of biological activity [2]. However, to our knowledge, only Guttiferone A has been tested for its antiplasmodial activity [3]. Phytochemical investigation of the trunk latex of Moronobea coccinea led to the isolation of twelve PPAPs. All compounds share the same type B phloroglucinol skeleton [4] and could be delineated by the position of their prenyl side chain and the presence of a tetrahydropyrane ring. Biological assay on Plasmodium falciparum chloroquin resistant strain (FCB1) showed IC50 from 3.3µM to 37.2µM. PPAPs with a tetrahydropyrane ring present the best antiplasmodial activity. Analysis of LC/UV/MS2 spectra of isolated PPAPs suggested some characteristics fragments for this chemical series. This hyphenated technique has been successfully applied on a bioactive extract from Symphonia sp, a close related species, and led to the isolation of eight new antiplasmodial PPAPs. This method constitutes an interesting tool for the structure prediction of type B PPAPs derivatives.

One new norlignan (1) and five new lignans (2-6) were isolated from the leaves and stems of Justicia patentiflora by a bioassay-guided purification. Five known compounds, carinatone, diphyllin, justicidin A, taiwanin E, and tuberculatin, were also found in J. patentiflora. Most of the new compounds display significant activity in in vitro cytotoxic assays against KB, HCT116, and MCF-7 cancer cell lines and arrest the cell cycle in the G(0)/G(1) phase.

A new bromoindolesulfonic acid derivative, echinosulfonic acid D (1) was isolated from the New-Caledonian sponge Psammoclemma sp. in a Minute quantity. The structure of the alkaloid was established by spectroscopic methods and, in particular, by ESI MSn experiments. Echinosulfonic acid D was cytotoxic to KB cells (IC50 2 mug/mL).

Eight new acylated triterpenoid saponins were isolated from the stem bark of Harpullia austro-caledonica along with the known harpuloside (9). Their structures were established using 1D and 2D NMR and mass spectrometry as 3-O-β-d-galactopyranosyl-(1 → 2)-β-d-glucuronopyranosyl-21β, 22α-di-O-angeloylbarringtogenol C (1), 3-O-α-l-rhamnopyranosyl-(1 → 3)-[β-d-galactopyranosyl-(1 → 2)]-β-d-glucuronopyranosyl-21β, 22α-di-O-angeloyl barringtogenol C (2), 3-O-α-l-arabinofuranosyl-(1 → 3)-[β-d-galactopyranosyl-(1 → 2)]-β-d-glucuronopyranosyl-21β, 22α-di-O-angeloylbarringtogenol C (3), 3-O-α-l-arabinofuranosyl-(1 → 2)-β-d-glucuronopyranosyl-21β, 22α-di-O-angeloylprotoaescigenin (4), 3-O-α-l-arabinofuranosyl-(1 → 3)-[α-l-arabinofuranosyl-(1 → 2)]-β-d-glucuronopyranosyl-21β, 22α-di-O-angeloyl protoaescigenin (5), 3-O-α-l-arabinofuranosyl-(1 → 3)-[β-d-xylopyranosyl-(1 → 2)]-β-d-glucuronopyranosyl-21β, 22α-di-O-angeloylprotoaescigenin (6), 3-O-α-l-arabinofuranosyl-(1 → 3)-[β-d-glucopyranosyl-(1 → 2)]-β-d-glucuronopyranosyl-21β, 22α-di-O-angeloylprotoaescigenin (7), 3-O-β-d-xylopyranosyl-(1 → 2)-β-d-glucuronopyranosyl-21β, 22α-di-O-angeloylprotoaescigenin (8). The EtOH extract of the stem bark showed in vitro cytotoxic activity against KB cells (90% at 10 μg/ml). At a concentration of 5 μg/ml, the saponin mixture showed haemolytic activity and caused 100% haemolysis of a 10% suspension of sheep erythrocytes.

Metabolism studies were conducted in order to investigate the reasons for the in vivo lack of activity of (-)-rhazinilam 1, an original poison of the mitotic spindle. Bioconversion by Beauveria bassiana strains, rat and human liver microsomes allowed the identification of metabolites 2, 3, and 4 oxidized in positions 3 and 5 of rhazinilam. Further experiments indicated that CYP2B6 was the main CYP responsible for the oxidation of 1 by human liver microsomes. All isolated metabolites were markedly less active than rhazinilam in vitro, which might explain its in vivo inactivity.

New rearranged polyprenylxanthones, namely garcibracteatone, neoisobractatins A and B, and xerophenone C were isolated from the leaves and bark of a vietnamese Garcinia, Garcinia bracteata, together with 5-O-methylxanthone V1, bracteaxanthones I and II, and the known nemorosonol and simple xanthones. Neoisobractatins A and B exhibit a significant cytotoxic activity on KB cells. A biogenetic hypothesis is proposed, which explains the possible origin of these so-called cage-xanthanoids.

A bioassay-guided purification of the extracts of Nothofagus dombeyi and N. pumilio leaves yielded several triterpenes and flavonoids including 2-O-acetylmaslinic acid, 3-O-acetyl 20,24,25-trihydroxydammarane, and 3,20,24,25-tetrahydroxydammarane as new natural products. All the isolated compounds were assessed for antifeeding activity against the 5th instar larvae of Ctenopsteustis obliquana. 12-Hydroxyoleanolic lactone and pectolinarigenin from N. dombeyi and dihydrooroxylin A from N. pumilio, showed significant antifeeding activity.

Nine new bidesmosidic 3-O-glucuronide oleanane triterpenoid saponins were isolated from the stem bark of Symplocos glomerata King along with two known saponins, salsoloside C and copteroside E, and two major lignans, (-)-pinoresinol and (-)-pinoresinol-4'-O-beta-D-glucopyranoside. The structures of the new saponins were established using one- and two-dimensional NMR spectroscopy and mass spectrometry as, 3-O-[beta-D-xylopyranosyl(1-->4)-[2-O-acetyl]-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, 3-O-[beta-D-xylopyranosyl(1-->4)-[3-O-acetyl]-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, 3-O-[beta-D-xylopyranosyl (1-->4)-[2,3-O-diacetyl]-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, 3-O-[alpha-L-arabinopyranosyl(1-->4)-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, 3-O-[alpha-L-arabinopyranosyl (1-->4)-[2-O-acetyl]-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, 3-O-[[beta-D-xylopyranosyl (1-->2)]-[beta-D-xylopyranosyl (1-->4)]-[3-O-acetyl]-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, 3-O-[[beta-D-glucopyranosyl (1-->2)]-[beta-D-xylopyranosyl (1-->4)]-[3-O-acetyl]-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, 3-O-[[beta-D-glucopyranosyl (1-->2)]-[alpha-L-arabinofuranosyl (1-->4)]-[3-O-acetyl]-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, and 3beta-O-[beta-D-xylopyranosyl(1-->4)-[2-O-acetyl]-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-morolic acid. The EtOH and EtOAc extracts of the stem bark showed no cytotoxic activity. At a concentration of 370 microg/ml, the saponin mixture showed haemolytic activity and caused 50% haemolysis of a 10% suspension of sheep erythrocytes.

In the course of automated screening for small-molecule agonists to peroxisome proliferator-activated receptor-γ (PPAR-γ), 10 new linear triterpenes 1–10 have been isolated from the bark of three neocaledonian Cupaniopsis species, SAPINDACEAE. The structures were elucidated by extensive mono- and bi-dimensional spectroscopy and mass spectrometry.

Six triterpenoid saponins were isolated from the stem bark of Pometia ridleyi along with two known saponins, acutoside A and calenduloside C. Their structures were established using one- and two-dimensional NMR and mass spectrometry as 3-O-beta-D-apiofuranosyl-(1-->3)-[beta-D-glucopyranosyl-(1-->2)]-beta-D-glucopyranosyl-, 3-O-beta-D-apiofuranosyl-(1-->3)-alpha-L-arabinopyranosyl-(1-->3)-[beta-D-glucopyranosyl-(1-->2)]-beta-D-glucopyranosyl-, 3-O-beta-D-apiofuranosyl-(1-->3)-beta-D-galactopyranosyl-(1-->3)-[beta-D-glucopyranosyl-(1-->2)]-beta-D-glucopyranosyl-, 3-O-alpha-L-arabinopyranosyl-(1-->3)-[beta-D-glucopyranosyl-(1-->2)]-alpha-L-arabinopyranosyl-, 3-O-beta-D-galactopyranosyl-(1-->3)-[beta-D-glucopyranosyl-(1-->2)]-alpha-L-arabinopyranosyl-, 3-O-beta-D-apiofuranosyl-(1-->3)-beta-D-galactopyranosyl-(1-->3)-[beta-D-glucopyranosyl-(1-->2)]-alpha-L-arabinopyranosyl-oleanolic acid. The EtOH and EtOAc extracts of the stem bark showed no cytotoxic activity. At a concentration of 23 microg/ml, the saponin mixture showed haemolytic activity and caused 50% haemolysis of a 10% suspension of sheep erythrocytes.

An extract of the fruits of Rhamnus nepalensis collected in Hoa Binh Province, Vietnam, was cytotoxic to KB cells. A bioassay-guided fractionation led to the isolation of a series of known anthraquinones and anthrones, one new rhamnosylanthraquinone, 3'-O-acetylfrangulin A (8), several new rhamnosylanthrones, the prinoidin-emodin bianthrones (9A-D), the prinoidin bianthrones (10A,B), and the rhamnepalins (11A-C). A structure-cytotoxic activity relationship study was performed on these isolates and some semisynthetic derivatives.

Bioassay-guided fractionation of a leaf extract of G. bracteata has yielded six new prenylxanthones, bractatin (1), isobractatin (2), 1-O-methylbractatin (3), 1-O-methylisobractatin (4), 1-O-methyl-8-methoxy-8,8a-dihydrobractatin (5), and 1-O-methylneobractatin (6). The structures of these compounds have been elucidated by spectroscopic means (NMR, MS), literature data, and X-ray crystallographic analysis of 2. These compounds possess significant cytotoxicity against the KB cell line.

Microtubule disassembly inhibitory properties have been established for the known polyisoprenylated benzophenones xanthochymol (1a) and guttiferone E (1b). The compounds were isolated from the fruits of Garcinia pyrifera collected in Malaysia. A structure-activity relationship study, including natural and semisynthetic derivatives, delineated some structural features necessary for the interaction with tubulin within this compound class.

Semi-synthesis of derivatives of rhazinilam, an antitubulin compound, delineated some molecular features necessary for biological activity. In the course of this study, the formation of rhazinilam from 1,2-didehydroaspidospermidine is reexamined and a new mechanism is proposed.

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Seeds and leaves of Aglaia argentea and bark of A. forbesii were extracted. The known cyclopentatetrahydrobenzofuran derivative rocaglaol (1) and the aminopyrrolidine odorine (5), were isolated together with nine new compounds: didesmethylrocaglamide (6), aglains A (7), B (8) and C (9), aglaforbesins A (10) and B (11), ethylrocaglaol (12) and forbaglins A (13) and B (14). Compounds 7–11 and 13,14 possess a new cyclopentatetrahydrobenzopyran and benzoxepine skeleton, respectively, linked to an odorine type moiety. All the structures were elucidated notably by 2D NMR spectroscopy. In addition, the structure of forbaglin A was established by X-Ray crystallographic analysis. Didesmethylrocaglamide revealed strong cytotoxic activity against KB cells (IC50 0.006 μg/ml).