The possible protective and curative effects of paeonol on carrageenan-induced acute hind paw edema in rats and dextran sulfate sodium (DSS)-induced colitis in mice have been evaluated. After oral administration, paeonol (20 and 40 mg/kg) reduced the edema increase in paw volumes and also the development of DSS-induced murine colitis. Furthermore, anti-inflammatory and anti-oxidant activities of paeonol (1) together with its 10 metabolites (M2~M11) were investigated by using in vitro anti-inflammatory and anti-oxidant assays. M3 and M11 exhibited significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities (with EC50 values of 93.44 and 23.24 μM, respectively). All the metabolites except M8 showed hydroxyl radical scavenging activities, and M3 and M11 were the most potent agents (with EC50 values of 336.02 and 124.05 μM, respectively). Inhibitory effects of paeonol, M2~M11 on the overproduction of nitric oxide (NO), and the release of TNF-α were also tested. M3 and M11 potently inhibited lipopolysaccharide (LPS)-induced overproduction of NO in macrophage RAW 264.7. Western blot results demonstrated that paeonol, M3, and M11 downregulated the high expression of inducible nitric oxide synthase (iNOS) and COX-2 proteins, and the effects of M3 and M11 were more potent when compared with paeonol. These findings indicated that paeonol may play anti-inflammatory and anti-oxidant roles by changing to its active metabolites after absorption. In addition, further investigations on the mechanism showed that paeonol, M3, and M11 blocked the phosphorylation of MAPK/ERK 1/2 and p38, whereas they showed no effect on the phosphorylation of JNK. The above results suggested that pre-treatment with paeonol might be an effective therapeutic intervention against inflammatory diseases including colitis.
Ginkgo biloba L., an ancient dioecious gymnosperm, is now cultivated worldwide for landscaping and medical purposes. A novel biflavonoid—amentoflavone 7''-O-β-D-glucopyranoside (1)—and four known biflavonoids were isolated and identified from the male flowers of Ginkgo. The anti-proliferative activities of five biflavonoids were evaluated on different cancer lines. Bilobetin (3) and isoginkgetin (4) exhibited better anti-proliferative activities on different cancer lines. Their effects were found to be cell-specific and in a dose and time dependent manner for the most sensitive HeLa cells. The significant morphological changes validated their anticancer effects in a dose-dependent manner. They were capable of arresting the G2/M phase of the cell cycle, inducing the apoptosis of HeLa cells dose-dependently and activating the proapoptotic protein Bax and the executor caspase-3. Bilobetin (3) could also inhibit the antiapoptotic protein Bcl-2. These might be the mechanism underlying their anti-proliferation. In short, bilobetin (3) and isoginkgetin (4) might be the early lead compounds for new anticancer agents.
A mild and efficient Cu(2)O-catalyzed domino intramolecular C-N coupling/C-Y (Y = O, S, N) bond formation was successfully achieved. Thus oxazino[3,2-a]indole, thiazino[3,2-a]indole and indolo[2,1-b]quinazoline derivatives were facilely assembled from readily accessible gem-dibromovinyl systems. The protocol is general and practical, affording a variety of the indole-incorporated products in good to excellent yields even under air atmosphere.
In mass spectrometry of protonated N-phenylcinnamides, the carbonyl oxygen is the thermodynamically most favorable protonation site and the added proton is initially localized on it. Upon collisional activation, the proton transfers from the carbonyl oxygen to the dissociative protonation site at the amide nitrogen atom or the α-carbon atom, leading to the formation of important reactive intermediates. When the amide nitrogen atom is protonated, the amide bond is facile to rupture to form ion/neutral complex 1, [RC(6)H(4)CH=CHCO(+)/aniline]. Besides the dissociation of the complex, proton transfer reaction from the α-carbon atom to the nitrogen atom within the complex takes place, leading to the formation of protonated aniline. The presence of electron-withdrawing groups favored the proton transfer reaction, whereas electron-donating groups strongly favored the dissociation (aniline loss). When the proton transfers from the carbonyl oxygen to the α-carbon atom, the cleavage of the C(α)-CONHPh bond results in another ion/neutral complex 2, [PhNHCO(+)/RC(6)H(4)CH=CH(2)]. However, in this case, electron-donating groups expedited the proton transfer reaction from the charged to the neutral partner to eliminate phenyl isocyanate. Besides the cleavage of the C(α)-CONHPh bond, intramolecular nucleophilic substitution (a nucleophilic attack of the nitrogen atom at the β-carbon) and stepwise proton transfer reactions (two 1,2-H shifts) also take place when the α-carbon atom is protonated, resulting in the loss of ketene and RC(6)H(5), respectively. In addition, the H/D exchanges between the external deuterium and the amide hydrogen, vinyl hydrogens and the hydrogens of the phenyl rings were discovered by D-labeling experiments. Density functional theory-based (DFT) calculations were performed to shed light on the mechanisms for these reactions.
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