Discovery of Anticancer Agents of Diverse Natural Origin.

Research progress from mainly over the last five years is described for a multidisciplinary collaborative program project directed toward the discovery of potential anticancer agents from a broad range of taxonomically defined organisms. Selected lead compounds with potential as new antitumor agents that are representative of considerable structural diversity have continued to be obtained from each of tropical plants, terrestrial and aquatic cyanobacteria, and filamentous fungi. Recently, a new focus has been on the investigation of the constituents of U.S. lichens and their fungal mycobionts. A medicinal chemistry and pharmacokinetics component of the project has optimized structurally selected lead natural products, leading to enhanced cytotoxic potencies against selected cancer cell lines. Biological testing has shown several compounds to have in vivo activity, and relevant preliminary structure-activity relationship and mechanism of action studies have been performed. Several promising lead compounds worthy of further investigation have been identified from the most recent collaborative work performed.

Update on Phytochemical and Biological Studies on Rocaglate Derivatives from Aglaia Species.

With about 120 species, Aglaia is one of the largest genera of the plant family Meliaceae (the mahogany plants). It is native to the tropical rainforests of the Indo-Australian region, ranging from India and Sri Lanka eastward to Polynesia and Micronesia. Various Aglaia species have been investigated since the 1960s for their phytochemical constituents and biological properties, with the cyclopenta[b]benzofurans (rocaglates or flavaglines) being of particular interest. Phytochemists, medicinal chemists, and biologists have conducted extensive research in establishing these secondary metabolites as potential lead compounds with antineoplastic and antiviral effects, among others. The varied biological properties of rocaglates can be attributed to their unusual structures and their ability to act as inhibitors of the eukaryotic translation initiation factor 4A (eIF4A), affecting protein translation. The present review provides an update on the recently reported phytochemical constituents of Aglaia species, focusing on rocaglate derivatives. Furthermore, laboratory work performed on investigating the biological activities of these chemical constituents is also covered.

Anti-HIV diphyllin glycosides from Justicia gendarussa.

In a search for new anti-HIV active leads from over several thousands of plant extracts, we have identified a potent plant lead. The active plant is determined as Justicia gendarussa (Acanthaceae), a medicinal plant that has been used for the treatment of injury, arthritis and rheumatism in Asia including China. Our bioassay-guided fractionation of the methanol extract of the stems and barks of the plant led to the isolation of two anti-HIV compounds, justiprocumins A and B. The compounds are identified as new arylnaphthalide lignans (ANL) glycosides. We further determined that the ANL glycosides are the chemical constituents that contribute to the anti-HIV activity of this plant. Justiprocumin B displayed potent activity against a broad spectrum of HIV strains with IC50 values in the range of 15-21 nM (AZT, IC50 77-95 nM). The compound also displayed potent inhibitory activity against the NRTI (nucleoside reverse transcriptase inhibitor)-resistant isolate (HIV-11617-1) of the analogue (AZT) as well as the NNRTI (non-nucleoside reverse transcriptase inhibitor)-resistant isolate (HIV-1N119) of the analogue (nevaripine).

Discovery of Bioactive Compounds by the UIC-ICBG Drug Discovery Program in the 18 Years Since 1998.

The International Cooperative Biodiversity Groups (ICBG) Program based at the University of Illinois at Chicago (UIC) is a program aimed to address the interdependent issues of inventory and conservation of biodiversity, drug discovery and sustained economic growth in both developing and developed countries. It is an interdisciplinary program involving the extensive synergies and collaborative efforts of botanists, chemists and biologists in the countries of Vietnam, Laos and the USA. The UIC-ICBG drug discovery efforts over the past 18 years have resulted in the collection of a cumulative total of more than 5500 plant samples (representing more than 2000 species), that were evaluated for their potential biological effects against cancer, HIV, bird flu, tuberculosis and malaria. The bioassay-guided fractionation and separation of the bioactive plant leads resulted in the isolation of approximately 300 compounds of varying degrees of structural complexity and/or biological activity. The present paper summarizes the significant drug discovery achievements made by the UIC-ICBG team of multidisciplinary collaborators in the project over the period of 1998-2012 and the projects carried on in the subsequent years by involving the researchers in Hong Kong.

Litsea Species as Potential Antiviral Plant Sources.

Litsea verticillata Hance (Lauraceae), a Chinese medicine used to treat swelling caused by injury or by snake bites, was the first plant identified by our National Institutes of Health (NIH)-funded International Cooperative Biodiversity Group (ICBG) project to exhibit anti-HIV activities. From this plant, we discovered a class of 8 novel litseane compounds, prototypic sesquiterpenes, all of which demonstrated anti-HIV activities. In subsequent studies, 26 additional compounds of different structural types were identified. During our continuing investigation of this plant species, we identified two new litseanes, litseaverticillols L and M, and a new sesquiterpene butenolide, litseasesquibutenolide. Litseaverticillols L and M were found to inhibit HIV-1 replication, with an IC[Formula: see text] value of 49.6[Formula: see text][Formula: see text]M. To further determine the antiviral properties of this plant, several relatively abundant isolates, including a litseane compound, two eudesmane sesquiterpenes and three lignans, were evaluated against an additional 21 viral targets. Lignans 8 and 9 were shown to be active against the Epstein-Barr Virus (EBV), with EC[Formula: see text] values of 22.0[Formula: see text][Formula: see text]M ([Formula: see text]) and 16.2[Formula: see text][Formula: see text]M ([Formula: see text]), respectively. Since many antiviral compounds have been discovered in L. verticillata, we further prepared 38 plant extracts made from the different plant parts of 9 additional Litsea species. These extracts were evaluated for their anti-HIV and cytotoxic activities, and four of the extracts, which ranged across three different species, displayed 97-100% inhibitory effects against HIV replication without showing cytotoxicity to a panel of human cell lines at a concentration of 20 µg/mL.

Bioassay-Guided Isolation and Structural Modification of the Anti-TB Resorcinols from Ardisia gigantifolia.

Tuberculosis (TB) is a highly contagious disease mainly caused by Mycobacterium tuberculosis H37 RV . Antitubercular (anti-TB) bioassay-guided isolation of the CHCl3 extract of the leaves and stems of the medicinal plant Ardisia gigantifolia led to the isolation of two anti-TB 5-alkylresorcinols, 5-(8Z-heptadecenyl) resorcinol (1) and 5-(8Z-pentadecenyl) resorcinol (2). We further synthesized 15 derivatives based on these two natural products. These compounds (natural and synthetic) were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37 RV . Resorcinols 1 and 2 exhibited anti-TB activity with MIC values at 34.4 and 79.2 µm in MABA assay, respectively, and 91.7 and 168.3 µm in LORA assay, respectively. Among these derivatives, compound 8 was found to show improved anti-TB activity than its synthetic precursor (2) with MIC values at 42.0 µm in MABA assay and 100.2 µm in LORA assay. The active compounds should be regarded as new hits for further study as a novel class of anti-TB agents. The distinct structure-activity correlations of the parent compound were elucidated based on these derivatives.

Isolation and characterization of minor analogues of silvestrol and other constituents from a large-scale re-collection of Aglaia foveolata.

Two new minor silvestrol analogues [2'''-episilvestrol (1) and 2''',5'''-diepisilvestrol (2)], together with a new 21-norbaccharane-type triterpene (3), two new 3,4-secodammarane triterpenes (4 and 5), and a new eudesmane sesquiterpene (6), as well as nine known compounds, were isolated from a large-scale re-collection of the CHCl(3)-soluble extract of the stem bark of Aglaia foveolata obtained in Kalimantan, Indonesia. The structures of the new compounds were established by interpretation of their spectroscopic data. All of the isolates were tested for cytotoxicity against HT-29 cells. The new silvestrol analogues, 1 and 2, were considerably less active as cytotoxic agents than silvestrol (7) and episilvestrol (5'''-episilvestrol) (8) against this cell line, showing the importance of the configuration at C-2''' in mediating such activity within this compound class. Several of the compounds isolated were also evaluated in a NF-κB (p65) inhibition assay.

Estrogenic and serotonergic butenolides from the leaves of Piper hispidum Swingle (Piperaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Our previous work has demonstrated that several plants in the Piperaceae family are commonly used by the Q'eqchi Maya of Livingston, Guatemala to treat amenorrhea, dysmenorrhea, and pain. Extracts of Piper hispidum Swingle (Piperaceae), bound to the estrogen (ER) and serotonin (5-HT7) receptors. AIM OF THE STUDY: To investigate the estrogenic and serotonergic activities of Piper hispidum extracts in functionalized assays, identify the active chemical constituents in the leaf extract, and test these compounds as agonists or antagonists of ER and 5-HT7. MATERIALS AND METHODS: The effects of the Piper hispidum leaf extracts were investigated in estrogen reporter gene and endogenous gene assays in MCF-7 cells to determine if the extracts acted as an estrogen agonist or antagonist. In addition, the active compounds were isolated using ER- and 5-HT7 receptor bioassay-guided fractionation. The structures of the purified compounds were identified using high-resolution LC-MS and NMR spectroscopic methods. The ER- and 5-HT7-agonist effects of the purified chemical constituents were tested in a 2ERE-reporter gene assay in MCF-7 cells and in serotonin binding and functionalized assays. RESULTS: Three butenolides including one new compound (1) were isolated from the leaves of Piper hispidum, and their structures were determined. Compound 1 bound to the serotonin receptor 5-HT(7) with IC(50) values of 16.1 and 8.3 microM, respectively, and using GTP shift assays, Compound 1 was found to be a partial agonist of the 5-HT(7) receptor. The Piper hispidum leaf extracts, as well as Compounds 2 and 3 enhanced the expression of estrogen responsive reporter and endogenous genes in MCF-7 cells, demonstrating estrogen agonist effects. CONCLUSIONS: Extracts of Piper hispidum act as agonists of the ER and 5-HT(7) receptors. Compound 1, a new natural product, identified as 9,10-methylenedioxy-5,6-Z-fadyenolide, was isolated as the 5-HT(7) agonist. Compounds 2 and 3 are reported for the first time in Piper hispidum, and identified as the estrogen agonists. No inhibition of CYP450 was observed for any of these compounds in concentrations up to 1 microM. These activities are consistent with the Q'eqchi traditional use of the plant for the treatment of disorders associated with the female reproductive cycle.

Bioactivity-guided isolation of cytotoxic sesquiterpenes of Rolandra fruticosa.

Cytotoxicity-guided fractionation of a methanol extract of the leaves and twigs of Rolandra fruticosa using the HT-29 human colon cancer cell line led to the isolation of seven sesquiterpene lactones, including the hitherto unknown isorolandrolide, 13-methoxyisorolandrolide (1), and bourbonenolide, 2alpha,13-diacetoxy-4alpha-hydroxy-8alpha-isobutyroyloxybourbonen-12,6alpha-olide (2), as well as five known compounds, 13-acetoxyrolandrolide (3), 8-desacyl-13-acetoxyrolandrolide-8-O-tiglate (4), 2-epi-glaucolide E (5), 2alpha,13-diacetoxy-4alpha-hydroxy-8alpha-methacryloyloxybourbonen-12,6alpha-olide (6), and 2alpha,13-diacetoxy-4alpha-hydroxy-8alpha-tigloyloxybourbonen-12,6alpha-olide (7). The structures of the two sesquiterpenes were elucidated on the basis of spectroscopic methods. All isolates were evaluated for their cytotoxicity using the HT-29 cell line, and only 13-acetoxyrolandrolide (3) was found to possess a potent inhibitory effect against this cell line. Compounds 3, 5 and 6 were also tested in a NF-kappaB (p65) inhibition assay, and 3 was assessed in an in vivo hollow fiber assay.

Medical potential of plants used by the Q'eqchi Maya of Livingston, Guatemala for the treatment of women's health complaints.

Investigation on the medical ethnobotany of the Q'eqchi Maya of Livingston, Izabal, Guatemala, was undertaken in order to explore Q'eqchi perceptions, attitudes, and treatment choices related to women's health. Through participant observation and interviews a total of 48 medicinal plants used to treat conditions related to pregnancy, childbirth, menstruation, and menopause were collected and identified followed by the evaluation of 20 species in bioassays relevant to women's health. Results of field interviews indicate that Q'eqchi cultural perceptions affect women's health experiences while laboratory results (estrogen receptor and serotonin receptor binding assays) provide a scientific correlation between empirical medicinal plant use among the Q'eqchi and the pharmacological basis for their administration. These data can contribute to Guatemala's national effort to promote a complementary relationship between traditional Maya medicine and public health services and can serve as a basis for further pharmacology and phytochemistry on Q'eqchi medicinal plants for the treatment of women's health conditions.

"Studies on biodiversity of Vietnam and Laos" 1998-2005: examining the impact.

The impact of the University of Illinois at Chicago-based Vietnam-Laos International Cooperative Biodiversity Group (ICBG) Program "Studies on Biodiversity of Vietnam and Laos", which has been in operation for the period of 1998-2005, touches on five major areas of endeavor: (a) biodiversity inventory and conservation; (b) studies on medicinal plants; (c) drug discovery and development; (d) economic development; and (e) issues on intellectual property rights and benefit sharing in natural products drug discovery and development. Highlights are presented and the significance is discussed.