Wilford Lie

A new protoberberine alkaloid from Meconopsis simplicifolia (D. Don) Walpers with potent antimalarial activity against a multidrug resistant Plasmodium falciparum strain

ETHNOPHARMACOLOGICAL RELEVANCE The aerial components of Meconopsis simplicifolia (D. Don) Walpers are indicated in Bhutanese traditional medicine for treating malaria, coughs and colds, and the infections of the liver, lung and blood. This study is to validate the ethnopharmacological uses of this plant and also identify potent antimalarial drug leads through bioassays of its crude extracts and phytochemical constituents. MATERIALS AND METHODS Meconopsis simplicifolia (D. Don) Walpers was collected from Bhutan and its crude MeOH extract was subjected to acid-base fractionation. Through repeated extractions, separations and spectroscopic analysis, the alkaloids obtained were identified and tested for their antimalarial and cytotoxicity activities. RESULTS Phytochemical studies resulted in the isolation of one new protoberberine type alkaloid which we named as simplicifolianine and five known alkaloids: protopine, norsanguinarine, dihydrosanguinarine, 6-methoxydihydrosanguinarine and oxysanguinarine. Among the five of the alkaloids tested, simplicifolianine showed the most potent antiplasmodial activities against the Plasmodium falciparum strains, TM4/8.2 (chloroquine-antifolate sensitive strain) and K1CB1 (multidrug resistant strain) with IC50 values of 0.78 μg/mL and 1.29 μg/mL, respectively. The compounds tested did not show any significant cytotoxicity activities against human oral carcinoma KB cells and normal Vero cells of African kidney epithelial cells. CONCLUSIONS This study validated the traditional uses of the plant for the treatment of malaria and identified a new alkaloid, simplicifolianine as a potential antimalarial drug lead.

Biological evaluation of bismuth non-steroidal anti-inflammatory drugs (BiNSAIDs): stability, toxicity and uptake in HCT-8 colon cancer cells.

Recent studies showed that the metal-coordinated non-steroidal anti-inflammatory drug (NSAID), copper indomethacin, reduced aberrant crypt formation in the rodent colon cancer model, while also exhibiting gastrointestinal sparing properties. In the present study, the stability and biological activity of three BiNSAIDs of the general formula [Bi(L)3]n, where L=diflunisal (difl), mefenamate (mef) or tolfenamate (tolf) were examined. NMR spectroscopy of high concentrations of BiNSAIDs (24h in cell medium, 37°C) indicated that their structural stability and interactions with cell medium components were NSAID specific. Assessment of cell viability using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium]bromide (MTT) assay showed that the toxicity ranking of the BiNSAIDs paralleled those of the respective free NSAIDs: diflH<mefH<tolfH. While the IC50 values of the BiNSAIDs (ranging between 16 and 81μM) were lower than the free NSAIDs, it was apparent that the toxicity of the BiNSAIDs was due to the molar ratio of the three NSAID molecules contained in the BiNSAIDs, with the exception of [Bi(difl)3]. The highest cellular bismuth content was observed following treatment with [Bi(tolf)3]. Since NMR studies indicated that [Bi(tolf)3] was the most stable BiNSAID and that cellular uptake of bismuth correlated with structural stability it appears that bismuth uptake is assisted by the NSAID. Microprobe SR-XRF imaging showed that the intracellular fate of bismuth was independent of the specific BiNSAID treatment whereby all BiNSAID-treated cells showed bismuth accumulation in the cytoplasm within 24-h exposure. The size and location of the hot spots (0.3-5.8μm(2)), were consistent with cellular organelles such as lysosomes.

Bioactive compounds from the roots of Strophioblachia fimbricalyx.

Eight new compounds, fimbricalyxs B-D (1-3), fimbricalyxanhydrides A and B (4, 5), and fimbricalyxlactones A-C (6-8), together with three known compounds, trigonostemone (9), 3,6,9-trimethoxyphenanthropolone (10), and fimbricalyx A (11), were isolated from the roots of Strophioblachia fimbricalyx. The structures of the new compounds were elucidated on the basis of their spectroscopic data and, in the case of compounds 2, 4, and 7, confirmed by single-crystal X-ray crystallographic analysis. Compounds 1-4 and 8 were evaluated for their cytotoxicity (KB, MCF7, and NCI-H187 cancer cells) and antiplasmodial activity (Plasmodium falciparum, K1 multidrug-resistant strain). Fimbricalyx B (1) exhibited potent antiplasmodial activity with an IC50 value of 0.019 μM, while 4 was cytotoxic toward NCI-H187 cancer cells and showed antiplasmodial activities with IC50 values of 5.7 and 3.9 μM, respectively. In addition, the X-ray structure of 10 and the antiplasmodial activity of 11 are reported herein for the first time.

Alkaloids from the roots of Stichoneuron caudatum and their acetylcholinesterase inhibitory activities.

Four new stichoneurine-type alkaloids, stichoneurines F and G (1-2) and sessilistemonamines E and F (3-4), have been isolated from the root extracts of Stichoneuron caudatum. The structures and relative configurations of these alkaloids have been determined by spectroscopic methods and molecular modeling experiments. Compounds 1-4 were tested for their acetylcholinesterase (AChE) inhibitory activities against human AChE. Compound 3 showed significant inhibitory activity with an IC50 value of 9.1±0.15 μM.

2-Phenylnaphthalenes and a polyoxygenated cyclohexene from the stem and root extracts of Uvaria cherrevensis (Annonaceae)

Three new 2-phenylnaphthalene derivatives, cherrevenaphthalenes A-C (1-3), and a new polyoxygenated cyclohexene derivative, (-)-uvaribonol F (4) together with six known compounds, 5-10, were isolated from the stem and root extracts of Uvaria cherrevensis (Annonaceae). The structures of all isolated compounds were elucidated by spectroscopic analysis. The structures of 3 and 4 were further confirmed by single crystal X-ray diffraction methods. Compound 2 exhibited modest antiplasmodial activity against the P. falciparum stains TM4/8.2 and K1CB1 with IC50 values of 18.8±3.63 and 23.4±4.08μM, respectively, and weak cytotoxicity to a Vero cell line. Furthermore, compound 4 displayed cytotoxic activity against a KB cell line with an IC50 value of 22.1±0.42μM but was non-cytotoxic to the Vero cell line. Compound 5 revealed stronger cytotoxicity towards the KB cell line, with an IC50 value of 5.05±0.86μM and was nearly equally cytotoxic to the Vero cell line.

Effect of multi-walled carbon nanotubes on the cross-linking density of the poly(glycerol sebacate) elastomeric nanocomposites

Processing conditions deeply affect the mechanical, chemical and biological properties of elastomeric based nanocomposites. In this work, multi-walled carbon nanotubes (MWCNTs) were dispersed in poly(glycerol sebacate) (PGS) prepolymer, followed by curing under vacuum at 120 °C. It was observed an increase of the water contact angle with the amount of MWCNTs added, as well as the tensile strength and Young modulus, without compromising the elastomeric behaviour of the pristine PGS matrix. The cross-linking degree was determined by the Flory-Rehner swelling method and through the mechanical rubber elasticity model, and an increase of more than six-fold was observed, which demonstrates the chemical conjugation between the MWCNTs and the PGS polymer chains, resulting in stiff and elastomeric nanocomposites. Finally, in vitro cell culture of adult mouse hypothalamus neurons A59 cells showed good support for cell viability and stimulation for axons and dendrites growth. The unique features of these nanocomposites make them promise for biomedical applications, as soft tissue substrates with tailored mechanical properties.