A novel flavonoid from Fissistigma cupreonitens, 5­hydroxy­7,8­dimethoxyflavanone, competitively inhibited the efflux function of human P-glycoprotein and reversed cancer multi-drug resistance.

BACKGROUND: P-glycoprotein (P-gp) over-expression plays a vital role in not only systemic drug bioavailability but also cancer multi-drug resistance (MDR). Develop functional inhibitors of P-gp can conquer both problems. PURPOSE AND STUDY DESIGN: The aim of the present study was to research the P-gp modulating effects and MDR reversing ability of a novel flavonoid from Fissistigma cupreonitens, the underlying inhibitory mechanisms were further elucidated as well. METHODS: Calcein-AM, rhodamine 123, and doxorubicin were fluorescent substrates for the evaluation of P-gp inhibitory function and detailed drug binding modes. Docking simulation was performed to reveal the in silico molecular bonding. ATPase assay and MDR1 shift assay were adopted to reveal the ATP consumption and conformational change of P-gp. The MDR reversing effects were demonstrated through cytotoxicity, cell cycle, and apoptosis analyses. RESULTS: 5­hydroxy­7,8­dimethoxyflavanone inhibited the efflux of rhodamine 123 and doxorubicin in a competitive manner, and increased the intracellular fluorescence of calcein at a concentration as low as 2.5 µg/ml. 5­hydroxy­7,8­dimethoxyflavanone slightly changed P-gp's conformation and only stimulated ATPase at very high concentration (100 µg/ml). The docking results showed that 5­hydroxy­7,8­dimethoxyflavanone and verapamil exhibited similar binding affinity to P-gp. The MDR reversing effects were prominent in the vincristine group, the reversal folds were 23.01 and 13.03 when combined with 10 µg/ml 5­hydroxy­7,8­dimethoxyflavanone in the P-gp over-expressing cell line (ABCB1/Flp-In™-293) and MDR cancer cell line (KB/VIN), respectively. CONCLUSION: The present study demonstrated that 5­hydroxy­7,8­dimethoxyflavanone was a novel effective flavonoid in the P-gp efflux inhibition and in vitro cancer MDR reversion.

Chemical Constituents of the Leaves of Peltophorum pterocarpum and Their Bioactivity.

Two new sesquiterpenoids peltopterins A and B (compounds 1 and 2) and fifty-two known compounds were isolated from the methanol extract of P. pterocarpum and their chemical structures were established through spectroscopic and mass spectrometric analyses. The isolates 40, 43, 44, 47, 48, 51 and 52 exhibited potential inhibitory effects of superoxide anion generation or elastase release.

Constituents from the leaves of Clausena lansium and their anti-inflammatory activity.

Five new acyclic amides, clausenalansamides C-G (1-5), clausenaline G (6) and (±)-5-(4-methylphenyl)-γ-valerolactone (7) reported from the natural source for the first time, were characterized from the leaves of Clausena lansium. Their structures were established by spectroscopic and spectrometric methods, and the absolute configurations of new compounds 1-5 were determined by electronic circular dichroism and single-crystal X-ray diffraction analyses. Eighteen compounds were evaluated for their anti-inflammatory activity and only imperatorin (11) and wampetin (12) displayed significant inhibition of fMLP/CB-induced superoxide anion generation with IC50 values of 1.7 ± 0.3 and 6.8 ± 1.1 µM, respectively.

Characterization of Cyclodepsipeptides from the Mycelium of Isariajaponica from Vietnam.

A new cyclodepsipeptide, isarin (1), was isolated from the insect pathogenic fungus Isaria japonica Yasuda, together with one known compound, beauveriolide 1 (2). The structure of this new compound was characterized using a combination of spectroscopic and spectrometric analyses.

Chemical constituents from the leaves of Annona reticulata and their inhibitory effects on NO production.

In the present study, the chemical investigation of the leaves of Annona reticulata has resulted in the identification of nine compounds, including annonaretin A, a new triterpenoid. The purified compounds were subjected to the examination of their effects on NO inhibition in LPS-activated mouse peritoneal macrophages and most of them exhibited significant NO inhibition, with IC50 values in the range of 48.6 ± 1.2 and 99.8 ± 0.4 µM.

Isolation and synthesis of melodamide A, a new anti-inflammatory phenolic amide from the leaves of Melodorum fruticosum.

Together with twelve known compounds (2-13), melodamide A (1), a new phenolic amide possessing p-quinol moiety, was purified and characterized from the methanolic extracts of the leaves of Melodorum fruticosum. The structure of melodamide A (1) was established with a combination of 2D NMR experiments, HR-ESI-MS and X-ray analyses. The other known compounds were identified by comparison of their spectroscopic and physical data with those reported in the literature. Moreover, some isolated compounds were examined for their inhibitory activity towards superoxide anion generation and elastase release in human neutrophils. Among the tested compounds, 1, 3, and 5 exhibited strong inhibition of superoxide anion generation with IC50 values ranging from 5.25 to 8.65 µM. Furthermore, synthesis and biological evaluation of melodamide A (1) and its analogs (14a-p) were described.

Bioactive constituents of Clausena lansium and a method for discrimination of aldose enantiomers.

Glycosides, clausenosides A and B, and carbazole alkaloids, clausenaline A, claulamine A, and claulamine B, together with 50 known compounds, were isolated from the stems of Clausena lansium. Their structures were determined by means of spectroscopic methods, including that of CD and 1D/2D NMR analysis. Claulamine A has a 1-oxygenated carbazole skeleton with a rare 2,3-lactone ring, and claulamine B represents an hitherto unknown acetal carbazole alkaloid. Thirty-one of the isolated known compounds were evaluated in various assays for anti-inflammatory activity. Among them, imperatorin, isoheraclenin, and osthol exhibited selective and potent inhibition of formyl-l-methionyl-l-leucyl-l-phenylalanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation, and lansiumarin C also decreased nitric oxide (NO) and tumor necrosis factor-α (TNF-α) production in lipopolysaccharide (LPS)-induced macrophages. In addition, a modified HPLC method of pre-column derivatization was developed that is more practical for simultaneous analysis of aldose enantiomers as compared to the literature method. The absolute configurations of the sugar moieties in clausenosides A and B were determined with this modified method.

The leaf essential oils of five Vietnamese Desmos species (Annonaceae).

The leaf essential oils of five Desmos species from Vietnam have been extracted by steam distillation and subjected to GC and GC-MS analyses. The plant samples were Desmos cochinchinensis Lour., D. penduculosus (A. DC.) Ban, D. penducolosus var. tonkinensis Ban, D. chinensis Lour., and D. dumosus (Roxb.) Saff. The oils were rich in sesquiterpene hydrocarbons (65.9%-88.9%) and monoterpene hydrocarbons (6.3%-30.9%). The oxygenated counterparts were less common. The quantitatively significant constituents of the oils were alpha-pinene (2.4%-12.1%), beta-elemene (2.2-39.5%), beta-caryophyllene (13.9-26.3%), germacrene D (9.9-15.5%), bicyclogermacrene (2.0-11.4%) and alpha-humulene (3.8-7.5%). The studied oils could be classified into two chemical forms: oils with abundance of beta-caryophyllene, germacrene D and alpha-pinene (D. cochinchinensis, D. penducolosus var. tonkinensis, D. chinensis and D. Dumosus) and oil with high amounts of beta-elemene, beta-caryophyllene and germacrene D (D. penduculosus).

Drimane-type sesquiterpenes with a dioxabicyclooctane skeleton from the fruiting bodies of Nigrofomes melanoporus and their cytotoxicity.

Two new drimane-type compounds, nigrofomins A ( 1) and B ( 2), possessing a rare dioxabicyclooctane moiety, were purified from the fruiting bodies of Nigrofomes melanoporus. Their structures were determined using 1D-, 2D-NMR and HR-ESI-MS spectroscopic analyses. In addition, 1 was established by X-ray crystallographic studies. Both nigrofomins A ( 1) and B ( 2) exhibited cytotoxicity on acute T-cell leukemia (Jurkat), human nasopharyngeal carcinoma (NPC-TW01), and lung cancer (NCI-H661) cells with IC (50) values in the range of 99.44-246.32 µM. Furthermore, the effects of 1 and 2 on cell-cycle progression of Jurkat cells displayed a concentration-dependent accumulation in the G (0)/G (1) phase.

The first bis-retrochalcone from Fissistigma latifolium.

Two novel chalconoids, [3-3'']bi-2-hydroxy-4,5,6-trimethoxydihydrochalcone (1) and 4,6-dimethoxy-2,5-quinodihydrochalcone (2), and twelve known compounds were isolated from the methanolic extract of Fissistigma latifolium (Dun.) Merr. The structures of all compounds were determined by spectroscopic methods. Of these, compounds 1, 2, and 2-hydroxy-4,5,6-trimethoxydihydrochalcone (10) belong to an uncommon group of chalconoids, the retrochalcones. Compound 1 is the first bis-retrochalcone to be reported, and compound 2 is a quinoretrochalcone. Furthermore, 2 showed activity against the MDA-MB-231 human breast cancer cell line with an IC (50) value of 7.1 µM.

Crotonkinins A and B and related diterpenoids from Croton tonkinensis as anti-inflammatory and antitumor agents.

Cytotoxicity-guided phytochemical investigation of a methanolic extract of Croton tonkinensis afforded two new kaurane diterpenoids (1, 2) and 10 known ent-kaurane-type diterpenoids (3- 12). The structures of 1 and 2 were based on analysis of spectroscopic and mass spectral data. Compounds 3- 12 were identified by comparison of their spectroscopic and physical data with those reported in the literature. Selected compounds from this plant were examined for cytotoxic and anti-inflammatory activities. Compounds 4 and 9 showed the highest cytotoxic activity against the tested tumor cell lines. Compounds 3, 4, 6, 8, 9, and 11 had IC 50 values less than 5 microM and were more potent than the nonspecific NOS inhibitor L-NAME in inhibiting LPS-induced NO production.