ABSTRACT
Latent HIV reservoirs are the main obstacle to eradicate HIV infection. One strategy proposes to eliminate these viral reservoirs by pharmacologically reactivating the latently infected T cells. We show here that a 4-deoxyphorbol ester derivative isolated from Euphorbia amygdaloides ssp. semiperfoliata, 4ß-dPE A, reactivates HIV-1 from latency and could potentially contribute to decrease the viral reservoir. 4ß-dPE A shows two effects in the HIV replication cycle, infection inhibition and HIV transactivation, similarly to other phorboids PKC agonists such PMA and prostratin and to other diterpene esters such SJ23B. Our data suggest 4ß-dPE A is non-tumorigenic, unlike the related compound PMA. As the compounds are highly similar, the lack of tumorigenicity by 4ß-dPE A could be due to the lack of a long side lipophilic chain that is present in PMA. 4ß-dPE activates HIV transcription at nanomolar concentrations, lower than the concentration needed by other latency reversing agents (LRAs) such as prostratin and similar to bryostatin. PKCθ/MEK activation is required for the transcriptional activity, and thus, anti-latency activity of 4ß-dPE A. However, CD4, CXCR4 and CCR5 receptors down-regulation effect seems to be independent of PCK/MEK, suggesting the existence of at least two different targets for 4ß-dPE A. Furthermore, NF-κb transcription factor is involved in 4ß-dPE HIV reactivation, as previously shown for other PKCs agonists. We also studied the effects of 4ß-dPE A in combination with other LRAs. When 4ß-dPE A was combined with another PKC agonists such as prostratin an antagonic effect was achieved, while, when combined with an HDAC inhibitor such as vorinostat, a strong synergistic effect was obtained. Interestingly, the latency reversing effect of the combination was synergistically diminishing the EC50 value but also increasing the efficacy showed by the drugs alone. In addition, combinations of 4ß-dPE A with antiretroviral drugs as CCR5 antagonist, NRTIs, NNRTIs and PIs, showed a consistent synergistic effect, suggesting that the combination would not interefer with antiretroviral therapy (ART). Finally, 4ß-dPE A induced latent HIV reactivation in CD4 + T cells of infected patients under ART at similar levels than the tumorigenic phorbol derivative PMA, showing a clear reactivation effect. In summary, we describe here the mechanism of action of a new potent deoxyphorbol derivative as a latency reversing agent candidate to decrease the size of HIV reservoirs.
Subject(s)
Anti-HIV Agents/pharmacology , HIV Infections/metabolism , HIV-1/physiology , Mitogen-Activated Protein Kinase Kinases/metabolism , Phorbol Esters/pharmacology , Protein Kinase C/metabolism , Virus Activation/drug effects , Vorinostat/pharmacology , Bryostatins/pharmacology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/virology , Cell Survival/drug effects , Drug Synergism , HIV Infections/pathology , HIV Infections/virology , HIV-1/drug effects , Humans , Jurkat Cells , Signal Transduction/drug effects , Virus Latency/drug effectsABSTRACT
Two new xanthones, caledonixanthone M 1 and caloxanthone L 2, and one new acid, caledonic acid 6 were isolated from the hexane-soluble extract of the stem bark of Calophyllum caledonicum. In the course of this phytochemical study, seven other known compounds - calothwaitesixanthone, calozeyloxanthone, allanxanthone, isoapetalic acid 3, calolongic acid 4, apetalic acid 5 and isocalolongic acid 7 - were isolated. Their antifungal activity against the growth of the human pathogenic fungus Aspergillus fumigatus was then investigated. The results indicated that the crude extract, calolongic acid 4 and isocalolongic acid 7 exhibited strong inhibitory effects with MIC (80) values of 8, 4, 2 microg/mL, respectively. Besides, calolongic acid 4, its lactone derivative 4a and isocalolongic acid 7 markedly reduced the respiration of pea seed mitochondria.
Subject(s)
Antifungal Agents/pharmacology , Calophyllum , Chromans/pharmacology , Electron Transport/drug effects , Phytotherapy , Antifungal Agents/administration & dosage , Antifungal Agents/therapeutic use , Aspergillus fumigatus/drug effects , Chromans/administration & dosage , Chromans/therapeutic use , Humans , Microbial Sensitivity Tests , Mitochondria/drug effects , Pisum sativum/metabolism , Plant Bark , Plant Extracts/administration & dosage , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , SeedsABSTRACT
Six new triterpenoid saponins have been isolated from the stem bark of Elattostachys apetala together with four known triterpenoid saponins. Three of these new compounds are glycosides of a newly described genin, 29-hydroxyhederagenin (1). On the basis of spectral evidence, the structures of the new saponins were concluded to be alpha-hederin 28-O-[alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranosyl] ester (2), sapindoside B 28-O-[alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranosyl] ester (3), 3-O-beta-D-xylopyranosyl astrantiasaponin VII (4), 3-O-[alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranosyl]-28-O-[beta-D-glucopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->6)]-beta-D-glucopyranosyl]-29-hydroxyhederagenin (5), 3-O-[alpha-L-arabinopyranosyl-(1-->3)-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranosyl]-28-O-[beta-D-glucopyranosyl(1-->2)-[beta-D-glucopyranosyl(1-->6)]-beta-D-glucopyranosyl]-29-hydroxyhederagenin (6), and 3-O-[beta-D-xylopyranosyl-(1-->3)-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranosyl]-28-O-[beta-D-glucopyranosyl-(1-->2)-beta-D-gluco pyranosyl-(1-->6)]-beta-D-glucopyranosyl]-29-hydroxyhederagenin (7).
Subject(s)
Rosales/chemistry , Saponins/chemistry , Triterpenes/chemistry , Carbohydrate Conformation , Carbohydrate Sequence , Glycosides/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Sequence Data , Oligosaccharides/chemistry , Oligosaccharides/isolation & purification , Plant Stems/chemistry , Saponins/isolation & purification , Triterpenes/isolation & purificationABSTRACT
The isolation of three saponins, 24-hydroxytormentic acid ester glucoside (1), niga-ichigoside F1 (2) and niga-ichigoside F2 (3), from the stem bark of Strasburgeria robusta, an endemic plant from New Caledonia, is reported.
Subject(s)
Magnoliopsida , Plants, Medicinal/chemistry , Saponins/chemistry , Humans , Magnetic Resonance Spectroscopy , Plant StemsABSTRACT
In a search for cancer chemopreventive agents from natural sources, chemical constituents of two kinds of Garcinia plants, Garcinia neglecta and Garcinia puat, collected in New Caledonia, were examined. Five new depsidones, garcinisidone-B (2), -C (3), -D (4), -E (5), and -F (6), were isolated, and their structures were determined by spectrometric analyses. Inhibitory effects of these depsidones on EBV-EA activation induced by TPA in Raji cells were also demonstrated.
Subject(s)
Ericales/chemistry , Ethers, Cyclic/isolation & purification , Plant Extracts/isolation & purification , Anticarcinogenic Agents , Antigens, Viral/metabolism , Depsides , Ethers, Cyclic/chemistry , Ethers, Cyclic/pharmacology , Herpesvirus 4, Human/drug effects , Humans , Lactones , Models, Chemical , New Caledonia , Plant Extracts/chemistry , Plant Extracts/pharmacology , Tetradecanoylphorbol Acetate/pharmacology , Tumor Cells, CulturedABSTRACT
Four new xanthones, caledonixanthones A-D (1-4), were isolated from the trunk bark of Calophyllum caledonicum, in addition to 17 known compounds. The structures of 1-4 were determined by means of spectroscopic analysis and chemical derivatization.
Subject(s)
Plants, Medicinal/chemistry , Xanthines/isolation & purification , Magnetic Resonance Spectroscopy , Molecular Conformation , Plant Epidermis/chemistry , Plant Extracts/chemistry , Spectrophotometry, UltravioletABSTRACT
A xanthone, montrouxanthone and a dihydroisocoumarin, montroumarin were isolated from the stem bark of Montrouziera sphaeroidea Pancher Ex Planchon et Triana [Guttiferae], along with two known compounds. Their structures were elucidated on the basis of spectroscopic analyses. This is the first report of the analysis of chemical constituents of Montrouziera species.
Subject(s)
Coumarins/isolation & purification , Plants, Medicinal/chemistry , Trees/chemistry , Xanthenes/isolation & purification , Xanthones , Chromatography, Thin Layer , Coumarins/chemistry , Magnetic Resonance Spectroscopy , New Caledonia , Xanthenes/chemistryABSTRACT
The leaves of Comptonella microcarpa have yielded one alkaloid, dictamnine, and four known polyoxygenated flavonoids, meliternatin, 3,5,8-trimethoxy-6,7-3',4'-dimethylenedioxyflavone, 7-(3-methylbut-2-enyloxy)-3,5,8-trimethoxy-3', 4'-methylenedioxyflavone (3), 7-hydroxy-3,5,8-trimethoxy-3', 4'methylenedioxyflavone. In addition, two new flavonoids were found whose structures were established on the basis of their spectral data as 7-hydroxy-3,5,6,8-tetramethoxy-3',4'-methylenedioxyflavone (1) and 7-(3-methylbut-2-enyloxy)-3,5,6,8-tetramethoxy-3', 4'-methylenedioxyflavone (2).
ABSTRACT
Four pyrrolizidine alkaloids, amphorogynines A-D (1-4), which belong to a new type having substituents at C-1 and C-6, were isolated from Amphorogyne spicata (Santalaceae). Their structures were elucidated by spectroscopic methods. The absolute stereochemistry (7aR) of the two main alkaloids, amphorogynines A and D, was determined using chemical correlations.
ABSTRACT
A new guanidine-type alkaloid, fontaineine (1), was isolated from the leaves of Fontainea pancheri and its structure elucidated by 2D NMR.