4-Quinolone alkaloids from Melochia odorata.

The methanol extract of Melochia odorata yielded three 4-quinolone alkaloids including waltherione A (1) and two new alkaloids, waltherione C (2) and waltherione D (3). Waltheriones A and C showed significant activities in an in vitro anti-HIV cytoprotection assay at concentrations of 56.2 and 0.84 µM and inhibition of HIV P24 formation of more than 50% at 1.7 and 0.95 µM, respectively. The structures of the alkaloids were established by spectroscopic data interpretation.

New antimycobacterial triterpenoids from Rhus taitensis.

Two new triterpenoids were isolated from the leaves and twigs of Rhus taitensis. Their structures were elucidated by 1D and 2D NMR spectroscopic studies as 1,10,24,25,30-pentahydroxysqualene and dammar-20(22),24-diene-3 ß,26,27-triol. Both compounds exhibited moderate antimycobacterial activities with an MIC of 45 µg/mL.

Antimycobacterial activity of Exocarpos latifolius is due to exocarpic acid.

Lipophilic fractions of stem extracts from Exocarpos latifolius, native to Papua New Guinea, showed significant activity against Mycobacterium tuberculosis H37Ra. Bioactivity-guided fractionation yielded exocarpic acid (E-octadeca-13-ene-9,11-diynoic-acid) as the major active component. Several new exocarpic acid analogs were also shown to be active. Exocarpic acid has previously been reported active against gram-positive, but not gram-negative bacteria. Work presented here demonstrates the selective activity of exocarpic acid against Mycobacterium tuberculosis H37Ra.

Tetrahdroxysqualene from Rhus taitensis shows antimycobacterial activity against Mycobacterium tuberculosis.

Tuberculosis has become a major health problem, in particular with the emergence of extremely drug resistant tuberculosis (XDRTB). In our search for new therapeutic leads against TB, we isolated a new triterpene (1) from the plant Rhus taitensis collected in Papua New Guinea. Tetrahydroxysqualene (1) was isolated using bioassay-guided fractionation of the methanolic extract of R. taitensis leaves and twigs. The structure of tetrahydroxysqualene (1) was elucidated on the basis of HRESIMS and 1D and 2D NMR spectra. Tetrahydroxysqualene (1) exhibited antituberculosis activity with an MIC of 10.0 microg/mL, while showing only modest cytotoxicity.

Development of a fluorescence-based assay to screen antiviral drugs against Kaposi's sarcoma associated herpesvirus.

Tumors associated with Kaposi's sarcoma-associated herpesvirus infection include Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Virtually all of the tumor cells in these cancers are latently infected and dependent on the virus for survival. Latent viral proteins maintain the viral genome and are required for tumorigenesis. Current prevention and treatment strategies are limited because they fail to specifically target the latent form of the virus, which can persist for the lifetime of the host. Thus, targeting latent viral proteins may prove to be an important therapeutic modality for existing tumors as well as in tumor prevention by reducing latent virus load. Here, we describe a novel fluorescence-based screening assay to monitor the maintenance of the Kaposi's sarcoma-associated herpesvirus genome in B lymphocyte cell lines and to identify compounds that induce its loss, resulting in tumor cell death.

Advanced applications of counter-current chromatography in the isolation of anti-tuberculosis constituents from Dracaena angustifolia.

Through several steps of in vitro based bioassay-guided fractionation, three highly potent anti-mycobacterial constituents (1-2 microg/mL minimum inhibitory concentrations) were isolated from Dracaena angustifolia Roxb. (Dracaenaceae). Isolation was expedited due to the application of new techniques in counter-current chromatography (CCC). The first of these applications, gradient-array CCC, enables the expansion of the high-resolution window (sweet spot) by applying successive CCC separations in different solvent systems to a crude extract. Further fractionation was also performed using the recently designed 1L fast-centrifugal partition chromatography (FCPC) rotor with the solvent system hexane:methyl-tert butylether:acetonitrile (10:1:10). Results indicated that gradient-array CCC and high-capacity FCPC can facilitate drug discovery efforts from complex natural products, increase reproducibility of separation schemes, and provide more rigid dereplication of previously isolated bioactive compounds.

Traditional Preparations and Methanol Extracts of Medicinal Plants from Papua New Guinea Exhibit Similar Cytochrome P450 Inhibition.

The hypothesis underlying this current work is that fresh juice expressed from Papua New Guinea (PNG) medicinal plants (succus) will inhibit human Cytochrome P450s (CYPs). The CYP inhibitory activity identified in fresh material was compared with inhibition in methanol extracts of dried material. Succus is the most common method of traditional medicine (TM) preparation for consumption in PNG. There is increasing concern that TMs might antagonize or complicate drug therapy. We have previously shown that methanol extracts of commonly consumed PNG medicinal plants are able to induce and/or inhibit human CYPs in vitro. In this current work plant succus was prepared from fresh plant leaves. Inhibition of three major CYPs was determined using human liver microsomes and enzyme-selective model substrates. Of 15 species tested, succus from 6/15 was found to inhibit CYP1A2, 7/15 inhibited CYP3A4, and 4/15 inhibited CYP2D6. Chi-squared tests determined differences in inhibitory activity between succus and methanol preparations. Over 80% agreement was found. Thus, fresh juice from PNG medicinal plants does exhibit the potential to complicate drug therapy in at risk populations. Further, the general reproducibility of these findings suggests that methanol extraction of dried material is a reasonable surrogate preparation method for fresh plant samples.

Interactions of Papua New Guinea medicinal plant extracts with antiretroviral therapy.

ETHNOPHARMACOLOGICAL RELEVANCE: A substantial proportion of the population in Papua New Guinea (PNG) lives with human immunodeficiency virus (HIV). Treatment requires lifelong use of antiretroviral therapy (ART). The majority of people in PNG use traditional medicines (TM) derived from plants for all types of health promotions. Consequently, there is a concern that herb-drug interactions may impact the efficacy of ART. Herb-drug, or drug-drug, interactions occur at the level of metabolism through two major mechanisms: enzyme induction or enzyme inhibition. In this study, extracts of commonly-used medicinal plants from PNG were screened for herb-drug interactions related to cytochrome P450s (CYPs). MATERIALS AND METHODS: Sixty nine methanol extracts of TM plants were screened for their ability to induce CYPs by human aryl hydrocarbon receptor- (hAhR-) and human pregnane X receptor- (hPXR-) dependent mechanisms, utilizing a commercially available cell-based luciferase reporter system. Inhibition of three major CYPs, CYP1A2, CYP3A4, and CYP2D6, was determined using human liver microsomes and enzyme-selective model substrates. RESULTS: Almost one third of the TM plant extracts induced the hAhR-dependent expression of CYP1A2, the hPXR-dependent expression of CYP3A4, or both. Almost two thirds inhibited CYP1A2, CYP3A4, or CYP2D6, or combinations thereof. Many plant extracts exhibited both induction and inhibition properties. CONCLUSIONS: We demonstrated that the potent and selective ability of extracts from PNG medicinal plants to affect drug metabolizing enzymes through induction and/or inhibition is a common phenomenon. Use of traditional medicines concomitantly with ART could dramatically alter the concentrations of antiretroviral drugs in the body; and their efficacy. PNG healthcare providers should counsel HIV patients because of this consequence.