Nguyen Manh Cuong

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.

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.

Mechanism of osthole inhibition of vascular Cav1.2 current

Osthole is a coumarin extracted from Cnidium monnieri (L.) Cusson. The medicinal plant is widely used in Vietnamese as well as Chinese traditional medicine as a vasodilating and antihypertensive agent. Here we have tested the proposition that the block of Ca(v)1.2 channels is mainly responsible for its vascular activity. An in-depth analysis of the effect of osthole on Ca(v)1.2 current (I(Ca1.2)) was performed in rat tail artery myocytes using the whole-cell patch-clamp method. Osthole decreased I(Ca1.2) in a concentration- and voltage-dependent manner. At holding potentials of -50 and -80mV, the pIC(50) values were 4.78±0.07 and 4.36±0.08, respectively; the latter corresponded to the drug apparent dissociation constant for resting channels, K(R), of 47.8μM. Osthole speeded up the inactivation kinetics of I(Ca1.2) and shifted the voltage dependence of the inactivation curve to more negative potentials in a concentration-dependent manner, with an apparent dissociation constant for inactivated channels (K(I)) of 6.88μM. Block of I(Ca1.2) was frequency-dependent and the rate of recovery from inactivation was slowed down. In conclusion, osthole is a vascular Ca(v)1.2 channel antagonist stabilizing the channel in its inactivated state. This mechanism may account for the systolic blood pressure reduction induced by the drug in animal models of hypertension and points to osthole as a lead for the development of novel antihypertensive agents.

Murrayafoline A attenuates the Wnt/β-catenin pathway by promoting the degradation of intracellular β-catenin proteins

Molecular lesions in Wnt/beta-catenin signaling and subsequent up-regulation of beta-catenin response transcription (CRT) occur frequently during the development of colon cancer. To identify small molecules that suppress CRT, we screened natural compounds in a cell-based assay for detection of TOPFalsh reporter activity. Murrayafoline A, a carbazole alkaloid isolated from Glycosmis stenocarpa, antagonized CRT that was stimulated by Wnt3a-conditioned medium (Wnt3a-CM) or LiCl, an inhibitor of glycogen synthase kinase-3beta (GSK-3beta), and promoted the degradation of intracellular beta-catenin without altering its N-terminal phosphorylation at the Ser33/37 residues, marking it for proteasomal degradation, or the expression of Siah-1, an E3 ubiquitin ligase. Murrayafoline A repressed the expression of cyclin D1 and c-myc, which is known beta-catenin/T cell factor (TCF)-dependent genes and thus inhibited the proliferation of various colon cancer cells. These findings indicate that murrayafoline A may be a potential chemotherapeutic agent for use in the treatment of colon cancer.

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.

Antioxidative and anti-inflammatory effect of quercetin and its glycosides isolated from mampat (Cratoxylum formosum)

In this study, quercetin, quercetin-3-O-β-d-glucopyranoside (isoquercitrin), quercetin-3-O-β-d-galactopyranoside (hyperin), and quercertin-3-O-α-l-rhamnoside (quercitrin) from mampat (Cratoxylum formosum) were isolated and their antioxidative and anti-inflammatory activities were investigated. Quercetin displayed weaker antioxidant activity than its glycosides, while the cellular antioxidant capacity of quercetin and hyperin was stronger than that of isoquercitrin and quercitrin, indicating that the higher cell-membrane permeability of quercetin and hyperin than isoquercitrin and quercitrin was due to the different hydrophobicity and the specific membrane receptor for galactose. The anti-inflammatory activity of quercetin was shown to be higher to its glycosides in nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) expression, and nuclear factor (NF)-κB activation, suggesting that quercetin inhibits NO production in LPS-stimulated RAW 264.7 cells via control of iNOS expression with attenuation of NF-κB activation. The data obtained in this study illustrates that the presence and kind of monosaccharide in quercetin glycosides may play a critical role in their cellular antioxidant and anti-inflammatory activities.

Glypetelotine, a sulphur-containing indole alkaloid from Glycosmis petelotii

Abstract A sulphur-containing indole alkaloid, glypetelotine, has been isolated from the leaves of the endemic Vietnamese plant Glycosmis petelotii Guill. (Rutaceae). The structure of glypetelotine was determined to be S -methyl N , N -2-[(1H)-indol-3-ethyl]-methyl thiocarbamate from the spectroscopic evidence including UV, IR, MS, 1 H - and 13 C -NMR, NOESY, HETCOR and DQF- 1 H – 1 H COSY. Conformational isomerism of the compound, resulting from the tertiary amide-like unit, was studied by dynamic 1 H -NMR spectroscopy carried out in different solvents and at different temperatures.

Oleanane-triterpenoids from Panax stipuleanatus inhibit NF-κB

In continuation of our research to find biological components from Panax stipuleanatus, four oleanane-type triterpenes (12 to 15) were isolated successively. Fifteen oleanane-type saponins (1 to 15) were evaluated for nuclear factor (NF)-κB activity using a luciferase reporter gene assay in HepG2 cells. Compounds 6 to 11 inhibited NF-κB, with IC50 values between 3.1 to 18.9 μM. The effects on inducible nitric oxide synthase and cyclooxygenase-2 by compounds 8, 10, and 11 were also examined using reverse transcription-polymerase chain reaction. Three compounds (8, 10, and 11) inhibited NF-κB activity by reducing the concentration of inflammatory factors in HepG2 cells.

1-O-Substituted derivatives of murrayafoline A and their antifungal properties

The synthesis of some 1-oxygenated derivatives of murrayafoline A (1) and their antifungal properties is reported. Three derivatives, 1-hydroxy-3-methyl-9H-carbazole (2), 1-(3-methylbut-2-enyloxy)-3-methyl-9H-carbazole (3) and 1-(2,3,4,6-tetra-O-acetyl-α-D-O-glucopyranosyl)-3-methyl-9H-carbazole (4) of murrayafoline A were synthesized. Compounds 1 and 2 exhibited strong fungicidal activity against Cladosporium cucumerinum at the dose of 12.5 µg.

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).