Ghee Teng Tan

Antimalarial Agents from Plants II. Decursivine, A New Antimalarial Indole Alkaloid from Rhaphidophora decursiva

Antimalarial bioassay-directed fractionation led to the isolation of a new active indole alkaloid, decursivine (1), from the leaves and stems of Rhaphidophora decursiva Schott (Araceae). In addition, a leaf sample yielded the structurally-related compound serotobenine (2), previously reported from a taxonomically unrelated family, which was not active against Plasmodium falciparum. The structure of 1 was elucidated by spectroscopic means, and its antimalarial activity was observed with IC 50 values of 3.93 and 4.41µg/ml against the D6 and W2 clones of Plasmodium falciparum, respectively.

HIV-1 and HIV-2 reverse transcriptases : a comparative study of sensitivity to inhibition by selected natural products

One hundred and fifty six pure natural products, which had previously been tested against HIV-1 reverse transcriptase, were evaluated for HIV-2 reverse transcriptase inhibitory activity. Compounds that lacked effect in the HIV-1 reverse transcriptase system were found also to be inactive against HIV-2 reverse transcriptase. However, compounds belonging to the benzophenanthridine and protoberberine classes of alkaloids, certain flavonoids, the iridoid, fulvoplumierin, and the ansamycin antibiotic, daunomycin, exhibited similar potencies in both enzyme systems. In contrast, HIV-2 reverse transcriptase was observed to be four-fold more sensitive toward the inhibitory effects of the ipecac alkaloids, O-methylpsychotrine sulfate heptahydrate and psychotrine dihydrogen oxalate. Such differences in susceptibilities to inhibitors may indicate subtle dissimilarities in enzyme structure and function.

Polyacetyleneginsenoside-Ro, a novel triterpene saponin from Panax ginseng

A new oleanolic acid-derived saponin, polyacetyleneginsenoside-Ro (1), was isolated along with the known ginsenosides-Ro methyl ester (2), -Rf, -Rg1, -Rg2, and gingerglycolipid B from the roots of Panax ginseng C. A. Meyer. The new saponin was identified as a ginsenoside-Ro derivative containing a polyacetylene side chain by spectroscopic means including 1D and 2D NMR, and was found to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) with an IC50 value of 13.4 μg/mL (11.1 μM).

Natural anti-HIV agents. Part 2: Litseaverticillol A, a prototypic litseane sesquiterpene from Litsea verticillata

Abstract We report herein the first isolation of a novel structural type sesquiterpene designated as ‘litseane’ from the twigs and leaves of Litsea verticillata Hance (Lauraceae). The isolate (litseaverticillol A, 1 ) was obtained as a racemate through bioassay-guided fractionation and found to inhibit the replication of human immunodeficiency virus (HIV) type 1 with an IC 50 value of 5.0 μg/mL (21.4 μM) and a selectivity index of 2.6. Spectroscopic data and a potential biosynthetic pathway are given.

Ethnobotanical approach versus random approach in the search for new bioactive compounds: Support of a hypothesis

Context: Whether natural product drug discovery programs should rely on wild plants collected “randomly” from the natural environment, or whether they should also include plants collected on the basis of use in traditional medicine remains an open question. Objective: This study analyzes whether plants with ethnomedical uses from Vietnam and Laos have a higher hit rate in bioassay testing than plants collected from a national park in Vietnam with the goal of maximizing taxonomic diversity (“random” collection). Materials and Methods: All plants were extracted and subjected to bioassay in the same laboratories. Results of assays of plant collections and plant parts (samples) were scored as active or inactive based on whether any extracts had a positive result in a bioassay. Contingency tables were analyzed using χ2 statistics. Results: Random collections had a higher hit rate than ethnomedical collections, but for samples, ethnomedical plants were more likely to be active. Ethnomedical collections and samples had higher hit rates for tuberculosis, while samples, but not collections, had a higher hit rate for malaria. Little evidence was found to support an advantage for ethnomedical plants in HIV, chemoprevention and cancer bioassays. Plants whose ethnomedical uses directly correlated to a bioassay did not have a significantly higher hit rate than random plants. Discussion: Plants with ethnomedical uses generally had a higher rate of activity in some drug discovery bioassays, but the assays did not directly confirm specific uses. Conclusions: Ethnomedical uses may contribute to a higher rate of activity in drug discovery screening.

Study of Antimalarial Activity of Chemical Constituents from Diospyros quaesita

Bioassay‐directed fractionation led to the isolation of seven compounds from a sample of the dried leaves, twigs, and branches of Diospyros quaesita Thw. (Ebenaceae). One of the isolates, betulinic acid 3‐caffeate (1), showed in vitro antimalarial activity against Plasmodium falciparum clones D6 (chloroquine‐sensitive) and W2 (chloroquine‐resistant) with IC50 values of 1.40 and 0.98 μM, respectively. Evaluation of compound 1 in the human oral epidermoid (KB) cancer cell line revealed cytotoxicity at ED50 of 4.0 μM. In an attempt to reduce the cytotoxicity of 1, the acetylated derivative 1a and betulinic acid (1b) were prepared. Of the seven isolates, diospyrosin (2) was determined to be a new neolignan. In addition to 1, other known compounds isolated in this study were pinoresinol, lariciresinol, N‐benzoyl‐L‐phenylalaninol, scopoletin, and poriferast‐5‐en‐3β,7α‐diol. The structure of 2 was elucidated based on spectroscopic data analysis including 1D‐ and 2D‐NMR, and HR‐ESI‐MS.

Sulfonic acid polymers are potent inhibitors of HIV-1 induced cytopathogenicity and the reverse transcriptases of both HIV-1 and HIV-2

Four novel sulfonic acid polymers were evaluated for their in vitro HIV-1 and HIV-2 reverse transcriptase (RT) inhibitory activity and found to be equipotent against both RTs. The aromatic polymers demonstrated IC50 values that were approximately 10(3)-fold lower than those observed with the aliphatic polymers. Among the aromatic polymers, poly(4-styrenesulfonic acid) (PSS) (MW 8000; IC50 = 0.02 microgram/ml) was 3-fold more potent than poly(anetholesulfonic acid) (PAS) of approximately the same molecular weight range. The activity of PSS polymers increased in proportion to the size of the polymers and, relative to suramin, activity could be enhanced over 200-fold. These polymers also inhibited the cytopathic effect of HIV-1 at concentrations that were non-toxic to MT-4 cells. The potent RT inhibitory properties of these stable sulfonic acid polymers suggest that structure-activity studies are warranted to yield agents capable of inhibiting multiple stages of the viral process.

An ethnobotanical survey of medicinal plants of Laos toward the discovery of bioactive compounds as potential candidates for pharmaceutical development

Context: An ethnobotany-based approach in the selection of raw plant materials to study was implemented. Objective: To acquire raw plant materials using ethnobotanical field interviews as starting point to discover new bioactive compounds from medicinal plants of the Lao People’s Democratic Republic. Methods: Using semi-structured field interviews with healers in the Lao PDR, plant samples were collected, extracted, and bio-assayed to detect bioactivity against cancer, HIV/AIDS, TB, malaria. Plant species demonstrating activity were recollected and the extracts subjected to a bioassay-guided isolation protocol to isolate and identify the active compounds. Results: Field interviews with 118 healers in 15 of 17 provinces of Lao PDR yielded 753 collections (573 species) with 955 plant samples. Of these 955, 50 extracts demonstrated activity in the anticancer, 10 in the anti-HIV, 30 in the anti-TB, and 52 in the antimalarial assay. Recollection of actives followed by bioassay-guided isolation processes yielded a series of new and known in vitro-active anticancer and antimalarial compounds from 5 species. Discussion: Laos has a rich biodiversity, harboring an estimated 8000–11,000 species of plants. In a country highly dependent on traditional medicine for its primary health care, this rich plant diversity serves as a major source of their medication. Conclusions: Ethnobotanical survey has demonstrated the richness of plant-based traditional medicine of Lao PDR, taxonomically and therapeutically. Biological assays of extracts of half of the 955 samples followed by in-depth studies of a number of actives have yielded a series of new bioactive compounds against the diseases of cancer and malaria.

Bioactive sulfated sesterterpene alkaloids and sesterterpene sulfates from the marine sponge Fasciospongia sp.

Two new sulfated sesterterpene alkaloids, 19-oxofasciospongine A (3) and fasciospongine C (4), and a new sesterterpene sulfate, 25-hydroxyhalisulfate 9 (5), along with two known sesterterpene sulfates, halisulfates 7 (6) and 9 (7), were isolated from an organic extract of the marine sponge Fasciospongia sp. The structures of the new compounds were established on the basis of one- and two-dimensional NMR spectroscopic studies as well as by HRESIMS analysis. Compounds 1-7 exhibited inhibitory activity against Streptomyces 85E in the hyphae-formation inhibition assay. Compounds 1, 2, and 4-7 were not cytotoxic when tested at 20 microg/mL with MCF-7, LNCaP, and LU cell lines. Only compound 3 demonstrated a moderate cytotoxic effect on the MCF-7 (IC(50) 13.4 microM), LNCaP (IC(50) 21.8 microM), and LU-1 cells (IC(50) 5.0 microM), respectively.

Bioactive compounds from Vitex leptobotrys

A new lignan, vitexkarinol (1), as well as a known lignan, neopaulownin (2), a known chalcone, 3-(4-hydroxyphenyl)-1-(2,4,6-trimethoxyphenyl)-2-propen-1-one (3), two known dehydroflavones, tsugafolin (4) and alpinetin (5), two known dipeptides, aurantiamide and aurantiamide acetate, a known sesquiterpene, vemopolyanthofuran, and five known carotenoid metabolites, vomifoliol, dihydrovomifoliol, dehydrovomifoliol, loliolide, and isololiolide, were isolated from the leaves and twigs of Vitex leptobotrys through bioassay-guided fractionation. The chalcone (3) was found to inhibit HIV-1 replication by 77% at 15.9 μM, and the two dehydroflavones (4 and 5) showed weak anti-HIV activity with IC50 values of 118 and 130 μM, respectively, while being devoid of cytotoxicity at 150 μM. A chlorophyll-enriched fraction of V. leptobotrys, containing pheophorbide a, was found to inhibit the replication of HIV-1 by 80% at a concentration of 10 μg/mL. Compounds 1 and 3 were further selected to be evaluated against 21 viral targets available at NIAID (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA).