Tai-Chi Wang

Thymol, Benzofuranoid, and Phenylpropanoid Derivatives: Anti-inflammatory Constituents from Eupatorium cannabinum

Five new compounds, 9-O-angeloyl-8,10-dehydrothymol (1), 9-(3-methylbutanoyl)-8,10-dehydrothymol (2), eupatobenzofuran (3), 2-hydroxy-2,6-dimethylbenzofuran-3(2H)-one (4), and 1-(2-hydroxy-4-methylphenyl)propan-1,2-dione (5), have been isolated from the aerial part of Eupatorium cannabinum subsp. asiaticum, together with 16 known compounds (6-21). Compounds 6-8, 11, 13, and 15 exhibited inhibition (IC50 values≤18.4 μM) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds 2, 3, 10, 13, and 15 inhibited fMLP/CB-induced elastase release with IC50 values≤18.3 μM.

Phthalides from Pittosporum illicioides var. illicioides with Inhibitory Activity on Superoxide Generation and Elastase Release by Neutrophils

Six new phthalides, (S)-3-ethyl-7-hydroxy-6-methoxyphthalide (1), (S)-3-ethyl-7-hydroxy-5,6-dimethoxyphthalide (2), (S)-3-ethyl-5,6,7-trimethoxyphthalide (3), (R)-3-ethyl-7-hydroxy-6-methoxyphthalide (4), (Z)-3-ethylidene-7-hydroxy-6-methoxyphthalide (5), and (Z)-3-ethylidene-6,7-dimethoxyphthalide (6), have been isolated from the root of Pittosporum illicioides var. illicioides, together with seven known compounds. The structures of these new compounds were determined through spectroscopic and MS analyses. Compounds 1-4 exhibited inhibition (IC50<or=29.8 microM) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds 5 and 6 inhibited fMLP/CB-induced elastase release with IC50 values of 38.6+/-4.3 and 33.9+/-3.9 microM, respectively.

New Labdane-Type Diterpenoids and Anti-Inflammatory Constituents from Hedychium coronarium

Four new labdane-type diterpenoids: hedychicoronarin (1), peroxycoronarin D (2), 7β-hydroxycalcaratarin A (3), and (E)-7β-hydroxy-6-oxo-labda-8(17),12-diene-15,16-dial (4), have been isolated from the rhizomes of Hedychium coronarium, together with 13 known compounds (5–17). The structures of these new compounds were determined through spectroscopic and MS analyses. Compounds 3, 5, 6, and 10 exhibited inhibition (IC50 values ≤4.52 μg/mL) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds 3–6, 10, and 11 inhibited fMLP/CB-induced elastase release with IC50 values ≤6.17 μg/mL.

Synthesis and antiproliferative evaluation of amide-containing flavone and isoflavone derivatives

Certain amide-containing flavone and isoflavone derivatives were synthesized and evaluated for their antiproliferative activities. These compounds were synthesized via alkylation of hydroxyl precursors followed by the reaction with H(2)SO(4) and NaN(3) (Schmidt reaction). The preliminary assays indicated that the inhibitory activity against the growth of NCI-H661 decreased in an order of linked chromophore flavone-6-yl 16a-d>flavone-7-yl 17a-d>flavone-3-yl 15a-d and isoflavone-7-yl 18a-d. Among these flavone-6-yl derivatives, N-(4-methoxyphenyl)-2-(4-oxo-2-phenyl-4H-chromen-6-yloxy)acetamide (16c) was the most potent with a GI(50) value of 0.84 microM. The inhibitory activity against the growth of NPC-TW01 decreased in an order of linked chromophore flavone-6-yl 16a-d>isoflavone-7-yl 18a-d>flavone-7-yl 17a-d>flavone-3-yl 15a-d. Flavone-6-yl derivatives 16a-d demonstrated significant inhibitory activities against the growth of NPC-TW01 cell with an average GI(50) value of 0.84 microM. The oxime derivatives 1 and 2 caused accumulation of NPC-TW01 cell in G(2)/M phase which were distinct from that of their amide isomers 16b and 16c, respectively, which induced cell-cycle arrest in G(0)/G(1) phase followed by apoptosis. Therefore, the antiproliferative mechanism of flavone derivatives was affected not only by the phenyl benzopyran-4-one pharmacophore but also by the peripheral substituents.

A New Indole Alkaloid and Anti-Inflammatory Constituents from Strychnos cathayensis

A new indole alkaloid, 11,12‐dimethoxyhenningsamine (1), was isolated from the roots of Strychnos cathayensis, together with 19 known compounds. The structure of this new compound was determined through spectroscopic and mass‐spectrometric analyses. Among the isolated compounds, 11‐methoxyhenningsamine (3) and aesculetin dimethyl ether (4) exhibited potent inhibition (IC50<5.5 μg/ml) on superoxide‐anion generation and elastase release by human neutrophils in response to fMet‐Leu‐Phe/cytochalasin B.

Novel oxime-bearing coumarin derivatives act as potent Nrf2/ARE activators in vitro and in mouse model

We have designed and synthesized certain novel oxime- and amide-bearing coumarin derivatives as nuclear factor erythroid 2 p45-related factor 2 (Nrf2) activators. The potency of these compounds was measured by antioxidant responsive element (ARE)-driven luciferase activity, level of Nrf2-related cytoprotective genes and proteins, and antioxidant activity. Among them, (Z)-3-(2-(hydroxyimino)-2-phenylethoxy)-2H-chromen-2-one (17a) was the most active, and more potent than the positive t-BHQ in the induction of ARE-driven luciferase activity. Exposure of HSC-3 cells to various concentrations of 17a strongly increased Nrf2 nuclear translocation and the expression level of Nrf2-mediated cytoprotective proteins in a concentration-dependent manner. HSC-3 cells pretreated with 17a significantly reduced t-BOOH-induced oxidative stress. In the animal experiment, Nrf2-mediated cytoprotective proteins, such as aldo-keto reductase 1 subunit C-1 (AKR1C1), glutathione reductase (GR), and heme oxygenase (HO-1), were obviously elevated in the liver of 17a-treated mice than that of control. These results suggested that novel oxime-bearing coumarin 17a is able to activate Nrf2/ARE pathway in vivo and are therefore seen as a promising candidate for further investigation.

(+)-(6aR,7R)-7-Hydroxy-N-Butyrylcaaverine, a New Aporphine Alkaloid from the Roots of Illigera luzonensis with Cytotoxic Activity

A new aporphine alkaloid, (+)-(6aR,7R)-7-hydroxy-N-butyrylcaaverine (1), has been isolated from the roots of Illigera luzonensis. The structure of the new compound1was determined through spectroscopic and MS analyses.

Discovery of oxime-bearing naphthalene derivatives as a novel structural type of Nrf2 activators.

Recent studies have demonstrated that oxidative stress insult is one of major causes of tumor formation. Therefore, identify the effective anti-oxidative agents as a preventive approach to stop cancer progression has widely explored. Although, many potent anti-oxidative ingredients in the natural products have been identified but the amount from the nature source hindrances the clinical application. Compound which can activate Nrf2 signaling pathway result unregulated the cellular antioxidant-responses has been demonstrated as an effective chemopreventive approach for cancer treatment. In the present study, certain oxime-bearing naphthalene derivatives were synthesized and evaluated for their Nrf2 activation and anti-proliferative activities. Results indicated (E)-1-(naphthalen-2-yloxy)propan-2-one oxime (11) which increased 2.04-fold Nrf2/ARE-driven luciferase activity was more active than its 1-substituted isomer 10 (1.17-fold) and t-BHQ (1.77-fold), the known Nrf2 activator. The activities were further increased by the replacement of the peripheral methyl group with the phenyl ring in which (Z)-2-(naphthalen-2-yloxy)-1-phenylethanone oxime (13a) exhibited 3.49-fold potency of the positive control. It is worth to mention that compounds 11, 13a, and 13b which showed significant Nrf2 activation are non-cytotoxic to the tested cells with IC50>50μM. This observation strongly suggested that these compounds can be used for chemoprevention. Mechanism studies indicated that these compounds were capable of inducing the phosphorylation of Nrf2 protein at serine 40 which led to the activation of the Nrf2 transcriptional activity.

Synthesis and antiproliferative activities of N-(naphthalen-2-yl)acetamide and N-(substituted phenyl)acetamide bearing quinolin-2(1H)-one and 3,4-dihydroquinolin-2(1H)-one derivatives

Certain N-(naphthalen-2-yl)acetamide and N-(substituted phenyl)acetamide bearing quinolin-2(1H)-one and 3,4-dihydroquinolin-2(1H)-one derivatives have been synthesized and evaluated in vitro for their antiproliferative activities against a panel of human cancer cell lines including nasopharyngeal (NPC-TW01), lung carcinoma (H661), hepatoma (Hep3B), renal carcinoma (A498), and gastric cancer (MKN45). Among them, N-(naphthalen-2-yl)-2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetamide (18) was the most active against NPC-TW01 with an IC(50) value of 0.6 μM. Studies on NPC-TW01 cell cycle distribution revealed that compound 18 inhibited proliferation of NPC-TW01 by the alteration of cell division, accumulation of cells in S phase in a time- and concentration-dependent manners. In addition, compound 18 demonstrated very specific cytotoxicity against human nasopharyngeal carcinoma (NPC-TW01) cell lines with no detectable cytotoxicity against peripheral blood mononuclear cells (PBMCs) at a concentration of up to 50 μM.

WTC‐01, a novel synthetic oxime‐flavone agent exerts potent microtubule‐destabilizing activity towards human nasopharyngeal carcinoma growth in vitro and in vivo

Dynamic polymerization of microtubules is essential for cancer cell growth and metastasis, and microtubule‐disrupting agents have become the most successful anti‐cancer agents in clinical use. Besides their antioxidant properties, flavonoids also exhibit strong microtubule‐disrupting activity and inhibit tumour growth. We have designed, synthesized and tested a series of oxime/amide‐containing flavone derivatives. Here we report the evaluation of one compound, WTC‐01 for its anti‐proliferative effects in human cancer cells.