Tigliane diterpenes from Croton mauritianus as inhibitors of chikungunya virus replication.

A bioassay-guided purification of an EtOAc extract of the leaves of Croton mauritianus using a chikungunya virus-cell-based assay led to the isolation of 12-O-decanoylphorbol-13-acetate (1) and the new 12-O-decanoyl-7-hydroperoxy-phorbol-5-ene-13-acetate (2), along with loliolide, vomifoliol, dehydrovomifoliol, annuionone D and bluemol C. The planar structure and the relative configuration of compound 2 were elucidated based on spectroscopic analysis, including 1D- and 2D-NMR experiments, mass spectrometry, and comparison with literature data. Compounds 1 and 2 inhibited chikungunya virus-induced cell death in cell culture with EC50s of 2.4±0.3 and 4.0±0.8 µM, respectively.

Cytotoxic aryltetralin lignans from fruits of Cleistanthus indochinensis.

Eight new aryltetralin lignans, cleisindosides A-F (1-6), picroburseranin (7), and 7-hydroxypicropolygamain (8), were isolated from the fruits of Cleistanthus indochinensis (Euphorbiaceae). The structures of the isolates were established on the basis of their one- and two-dimensional NMR spectral data, as well as their mass spectrometric data. Compound 7 was found to have potent cytotoxicity against oral epidermoid carcinoma cells with an IC50 value of 0.062 µM, whereas glycosylation to 3 (IC50 7.5 µM) and stereochemical changes to 8 (IC50 10.8 µM) led to marked decreases in biological activity. Thus, it was determined that the C-7 and C-8' positions are critical for the biological activity of the lignans from this plant.

Styryllactones and acetogenins from the fruits of Goniothalamus macrocalyx.

Two new styryllactones, macrocalactone (1) and 3-deoxycardiobutanolide (2), were isolated from the fruits of Goniothalamus macrocalyx Ban (Annonaceae), together with seven known compounds including four acetogenins, annonacin (3), solamin (4), isoannonacin (5), trans-murisolinone (6), and three other compounds, 7-acetylaltholactone (7), beta-caryophyllene-8R,9R-oxide (8) and 2-(2'-hydroxytetracosanoylamino)-octadecane-1,3,4-triol (9). Their structures were determined by spectroscopic and MS analysis. The absolute configuration of 1 was determined by X-ray crystallographic analysis. The structures of the acetogenins were confirmed by liquid chromatography coupled to a hybrid quadrupole-time of flight mass spectrometer, using post-column lithium infusion. The results were compared with the fragmentation obtained with a hybrid linear trap-orbitrap mass spectrometer. Compound 7 had cytotoxicity against KB, HepG2, Lu, and MCF7 cell lines with IC50 values of 13.1, 23.7, 26.3 and 60.2 microM, respectively, whereas annonacin (3) was selectively active against KB cells (IC50 value of 6.5 microM). The discovery of 3-deoxycardiobutanolide (2) from the fruits of this plant revealed that G. macrocalyx could be a valuable natural resource to obtain this compound as it has been previously reported to have a significant cytotoxicity against different cancer cell lines, especially HL-60 cells.

Kingianic acids A-G, Endiandric acid analogues from Endiandra kingiana.

A phytochemical investigation of the methanolic extract of the bark of Endiandra kingiana led to the isolation of seven new tetracyclic endiandric acid analogues, kingianic acids A-G (1-7), together with endiandric acid M (8), tsangibeilin B (9) and endiandric acid (10). Their structures were determined by 1D- and 2D-NMR analysis in combination with HRMS experiments. The structure of compounds 9 and 10 were confirmed by single-crystal X-ray diffraction analysis. These compounds were screened for Bcl-xL and Mcl-1 binding affinities and cytotoxic activity on various cancer cell lines. Compound 5 showed moderate cytotoxic activity against human colorectal adeno-carcinoma (HT-29) and lung adenocarcinoma epithelial (A549) cell lines, with IC50 values in the range 15-17 µM, and compounds 3, 6 and 9 exhibited weak binding affinity for the anti-apoptotic protein Mcl-1.

Natural aristolactams and aporphine alkaloids as inhibitors of CDK1/cyclin B and DYRK1A.

In an effort to find potent inhibitors of the protein kinases DYRK1A and CDK1/Cyclin B, a systematic in vitro evaluation of 2,500 plant extracts from New Caledonia and French Guyana was performed. Some extracts were found to strongly inhibit the activity of these kinases. Four aristolactams and one lignan were purified from the ethyl acetate extracts of Oxandra asbeckii and Goniothalamus dumontetii, and eleven aporphine alkaloids were isolated from the alkaloid extracts of Siparuna pachyantha, S. decipiens, S. guianensis and S. poeppigii. Among these compounds, velutinam, aristolactam AIIIA and medioresinol showed submicromolar IC50 values on DYRK1A.

Chemical constituents of Anacolosa pervilleana and their antiviral activities.

In an effort to identify novel inhibitors of Chikungunya (CHIKV) and Dengue (DENV) virus replication, a systematic study with 820 ethyl acetate extracts of Madagascan plants was performed in a virus-cell-based assay for CHIKV and a DENV NS5 RNA-dependant RNA polymerase (RdRp) assay. The extract obtained from the leaves of Anacolosa pervilleana was selected for its significant activity in both assays. One new (E)-tridec-2-en-4-ynedioic acid named anacolosine (1), together with three known acetylenic acids, the octadeca-9,11,13-triynoic acid (2), (13E)-octadec-13-en-9,11-diynoic acid (3), (13E)-octadec-13-en-11-ynoic acid (4), two terpenoids, lupenone (5) and ß-amyrone (6), and one cyanogenic glycoside, (S)-sambunigrin (7) were isolated. Their structures were elucidated by comprehensive analyses of NMR spectroscopy and mass spectrometry data. The inhibitory potency of these compounds was evaluated on CHIKV, DENV RdRp and West-Nile polymerase virus (WNV RdRp). Both terpenoids showed a moderate activity against CHIKV (EC(50) 77 and 86 µM, respectively) and the acetylenic acids produced IC(50) values around 3 µM in the DENV RdRp assay.

Toxicarioside M, a new cytotoxic 10ß-hydroxy-19-nor-cardenolide from Antiaris toxicaria.

A new 10ß-hydroxy-19-nor-cardenolide, named toxicarioside M (1), was isolated from the trunk bark of Antiaris toxicaria (Pers.) Lesch (Moraceae), along with six known cardenolides (convallatoxin (2), convallatoxol (3), convalloside (4), 3-O-ß-D-xylopyranosylstrophanthidin (5), glucostrophanthidin (6) and strophanthidin (7)). Their structures were elucidated on the basis of HR-MS(n) analysis, spectroscopic methods (IR, UV, 1D and 2D NMR) and by comparison with data reported in the literature. The cardenolides were evaluated for their cytotoxic activity against KB, HCT-116, SF-268, MCF-7, HL-60, PC-3 and MRC-5 cell lines.

A new xanthone from the bark extract of Rheedia acuminata and antiplasmodial activity of its major compounds.

Bioassay-guided fractionation of the ethyl acetate bark extract of Rheedia acuminata led to the isolation of the new compound 1,5,6-trihydroxy-3-methoxy-7-geranyl-xanthone, together with four known compounds. These compounds were tested in vitro for their antiplasmodial activity on a chloroquine-resistant strain of Plasmodium falciparum (FcB1) and for their cytotoxicity against the human diploid embryonic lung cell line MRC-5.

Cytotoxic prenylated isoflavone and bipterocarpan from Millettia pachyloba.

Two new compounds, an isoflavone (1, 6-methoxybarbigerone) and a bipterocarpan (2, pachylobin) were isolated from the grains of Millettia pachyloba (Leguminosae), together with seven known compounds, 5-methoxybarbigerone (3), calopogoniumisoflavone B (4), durmillone (5), jamaicin (6), ichthynone (7), (-)-pisatin (8) and (-)-rotenone (9). The structures were established from spectroscopic analyses, including mass spectrometry and 2D-NMR. Absolute configuration of 2 was proposed based on that of the known compound (-)-pisatine (8). Compounds 1 and 2 exhibited cytotoxicity against KB cells with IC(50) values of 2.0 and 17.6 µM, respectively.

Antiplasmodial benzophenone derivatives from the root barks of Symphonia globulifera (Clusiaceae).

In an effort to find antimalarial drugs, a systematic in vitro evaluation on a chloroquine-resistant strain of Plasmodium falciparum (FcB1) was undertaken on sixty plant extracts collected in French Guiana. The ethyl acetate extract obtained from the root barks of Symphonia globulifera exhibited a strong antiplasmodial activity (97% at 10 microg/ml). The phytochemical investigation of this extract led to the isolation of nine polycyclic polyprenylated acylphloroglucinol (PPAPs) compounds and two oxidized derivatives. All compounds showed antiplasmodial activity with IC(50)s ranged from 2.1 to 10.1 microM. A LC/ESI-MS(n) study performed on polyprenylated benzophenones previously isolated from Moronobea coccinea provided a reliable method for their detection in the extract and structural elucidation.

Antiplasmodial, antitrypanosomal, and cytotoxic activities of prenylated flavonoids isolated from the stem bark of Artocarpus styracifolius.

In continuation of our efforts to find new antimalarial drugs, a systematic IN VITRO evaluation using a chloroquine resistant strain of PLASMODIUM FALCIPARUM (FcB1) was undertaken on extracts prepared from various parts of Vietnamese plants. The ethyl acetate extract obtained from the stem bark of ARTOCARPUS STYRACIFOLIUS (Moraceae) exhibited strong antiplasmodial activity (87 % at 10 µg/mL) whereas weak cytotoxicity was observed in a human fibroblast cell line (MRC-5). Phytochemical investigation of this extract led to isolation of two new prenylated flavonoids, styracifolins A and B ( 1 and 2), as well as the known artoheterophyllin A ( 3) and B ( 4), artonins A ( 5), B ( 6), and F ( 7), and heterophyllin ( 8). Structures of 1 and 2 were elucidated by spectroscopic methods and through comparison with data reported in the literature. Compounds 1- 8 exhibited antiplasmodial activities with IC (50) values ranging from 1.1 µM to 13.7 µM, and compounds 1, 2, 6, and 8 showed significant antitrypanosomal activities.

Identification of allosteric inhibitors blocking the hepatitis C virus polymerase NS5B in the RNA synthesis initiation step.

Hepatitis C virus (HCV) RNA-dependent RNA polymerase NS5B constitutes a target of choice for the development of anti-HCV drugs. Although many small molecules have been identified as allosteric inhibitors of NS5B, very few are active in clinical applications. We have screened 17,000 compounds in an enzymatic assay involving the purified NS5B in order to increase the therapeutic arsenal. We hoped to shed some light on the precise mechanism of RNA synthesis. We succeeded in isolating a series of 21 original inhibitors of the RNA synthesis by NS5B. Four of these non-nucleoside inhibitors (NNIs) could be mapped to the known binding site called 'B' as judged by the decrease in their inhibition potency when assayed with a 'B' site mutant, M423T NS5B. Incidentally, our in silico model pointed to Y477 as a key residue for inhibitor binding. In vitro, Y477F mutant loses its sensitivity to the newly discovered inhibitors but is unable to extend primers during the elongation phase. Our results demonstrate that elements of the 'B' site are involved in the conformational changes required in the switch between the different RNA synthesis steps and that compounds targeting this site could lock the enzyme in its initiation phase.

Cytotoxic pentacyclic triterpenoids from Combretum sundaicum and Lantana camara as inhibitors of Bcl-xL/BakBH3 domain peptide interaction.

In an effort to discover potent inhibitors of the antiapoptotic protein Bcl-xL, a systematic in vitro evaluation was undertaken on extracts prepared from various parts of Vietnamese plants. The ethyl acetate extracts obtained from the leaves and flowers of Combretum sundaicum and the leaves of Lantana camara were selected for their interaction with the Bcl-xL/Bak association. Bioassay-guided purification of these species led to the isolation of 15 pentacyclic triterpenoids (1-15) possessing olean-12-en-28-oic acid and olean-12-en-29-oic acid aglycons, of which compounds 1-6 and 8-10 are new. Five compounds exhibited binding activity with K(i) values between 5.3 and 17.8 microM. The cytotoxic activity of 1-15 was also evaluated on various cancer cell lines.

A Dimeric sesquiterpenoid from a Malaysian Meiogyne as a new inhibitor of Bcl-xL/BakBH3 domain peptide interaction.

In an effort to find potent inhibitors of the antiapoptotic protein Bcl-xL, a systematic in vitro evaluation was undertaken on 1470 Malaysian plant extracts. The ethyl acetate extract obtained from the bark of Meiogyne cylindrocarpa was selected for its interaction with the Bcl-xL/Bak association. Bioassay-guided purification of this species led to the isolation of two new dimeric sesquiterpenoids (1 and 2) possessing an unprecedented substituted cis-decalin carbon skeleton. Meiogynin A (1) showed the strongest activity with a K(i) of 10.8 +/- 3.1 microM.

Antiplasmodial benzophenones from the trunk latex of Moronobea coccinea (Clusiaceae).

In an effort to find antimalarial drugs, a systematic in vitro evaluation on a chloroquine-resistant strain of Plasmodium falciparum (FcB1) was undertaken on sixty plant extracts collected in French Guiana. The methanol extract obtained from the latex of Moronobea coccinea exhibited a strong antiplasmodial activity (95% at 10microg/ml). The phytochemical investigation of this extract led to the isolation of eleven polycyclic polyprenylated acylphloroglucinols (PPAPs), from which eight showed potent antiplasmodial activity with IC50 ranged from 3.3microM to 37.2microM.

Antiplasmodial alkaloids from Desmos rostrata.

Two new alkaloids, desmorostratine (1) and discretine N-oxide (2), were isolated from the stem bark of Desmos rostrata, together with five known alkaloids, discretine (3), dehydrodiscretine (4), pseudocolumbamine (5), predicentrine (6), and aristolactam AII (7). The structures were established on the basis of spectroscopic data, including mass spectrometry and 2D-NMR. Compound 1 was cytotoxic against KB cells (IC(50) 2.4 microM), while 2, 3, and 4 inhibited Plasmodium falciparum (IC(50) of 4.2, 1.6, and 0.9 microM, respectively).

Acylphenols from Myristica crassa as new acetylcholinesterase inhibitors.

A significant acetylcholinesterase inhibitory activity was observed for the ethyl acetate and methanol extracts from the leaves and the fruits of MYRISTICA CRASSA. Three new dimeric acylphenols, giganteone C ( 5), maingayones B and C ( 6 and 7) were isolated together with the known malabaricones B and C ( 2 and 3) and giganteone A ( 4). Compounds 2 and 3 possess significant inhibitory activity on acetylcholinesterase. LC/MS study was particularly useful to discriminate structures of compounds 6 and 7.

Sesquiterpenoids and cytotoxic lignans from the bark of Libocedrus chevalieri.

Investigation of an EtOAc extract of the bark of Libocedrus chevalieri led to the isolation of a new cytotoxic lignan, 5-methoxy-4-epipodophyllotoxin (1), and three known podophyllotoxin analogues, 5-methoxypodophyllotoxin, 5-methoxypodophyllotoxin-4-O-beta-D-glucoside, and podophyllotoxin-4-O-beta-D-glucoside. Six sesquiterpenoids and a diterpenoid were also obtained. Of these, compounds 2-4 are new sesquiterpenoids, named libocedrines A-C, and 3beta-hydroxyilicic alcohol was isolated for the first time from a higher plant. Structures of the new compounds were determined on the basis of spectroscopic methods. Cytotoxicity of the isolated compounds against KB and L1210 cells and their effects on tubulin assembly were evaluated.

Cytotoxic farnesyl glycosides from Pittosporum pancheri.

Bioassay guided purification of the ethanolic extract of the bark of New Caledonian Pittosporum pancheri Brongn. and Gris (Pittosporaceae) led to the isolation and characterization of two new farnesyl monoglycosides, pancherins A and B. The structure of these compounds were determined on the basis of spectroscopic studies. The new compounds displayed a significant activity in the in vitro cytotoxic assay against KB cancer cell line, and pancherin A inhibits weakly farnesyl protein transferase.

Cytotoxic monotetrahydrofuran acetogenins from Disepalum plagioneurum.

The known plagionicin A (1) and eight new monotetrahydrofuran acetogenins, plagionicins B-D (2-4) and plagioneurins A-E (5-9), were isolated from the leaves of Disepalum plagioneurum by bioassay-guided purification. The structures of the new compounds were elucidated by spectroscopic methods. The new monotetrahydrofuran (mono-THF) acetogenins exhibited significant in vitro cytotoxicity against the KB cancer cell line, with IC(50) values in the nanomolar range.