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A series of chromatographic separations performed on the ethanol extracts of the peels of Citrus grandis has led to the characterization of forty compounds, including seventeen coumarins, eight flavonoids, two triterpenoids, four benzenoids, two steroids, one lignan, one amide, and five other compounds, respectively. The chemical structures of the purified constituents were identified on the basis of spectroscopic elucidation, including 1D- and 2D-NMR, UV, IR, and mass spectrometric analysis. Most of the isolated compounds were examined for their inhibition of superoxide anion generation and elastase release by human neutrophils. Among the isolates, isomeranzin (3), 17,18-dihydroxybergamottin (12), epoxybergamottin (13), rhoifolin (19), vitexicarpin (22) and 4-hydroxybenzaldehyde (29) displayed the most significant inhibition of superoxide anion generation and elastase release with IC50 values ranged from 0.54 to 7.57 μM, and 0.43 to 4.33 μM, respectively. In addition, 7-hydroxy-8-(2′-hydroxy-3′-methylbut-3′-enyl)coumarin (8) and 17,18-dihydroxybergamottin (12) also exhibited the protection of neurons against Aβ-mediated neurotoxicity at 50 μM.

Twelve novel 20-sulfonylamidine derivatives (9a–9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.

Inducible NO synthase (iNOS) NF-jB RAW 264.7 monocyte/macrophages Lipopolysaccharide (LPS) Mitogen-activated protein kinase (MAPK) Phosphatidylinositol 3-kinase (PI3K)Magnolol is a hydroxylated biphenyl compound from the bark of Magnolia officinalis that has been reported to have various biological properties including anti-inflammation. However, the molecular mechanism of anti-inflammation remains unclear although it has been suggested that magnolol inhibits NO production in murine macrophage. In this study, we investigated the inhibitory effects of magnolol on the induction of NO synthase (NOS) and COX-2 in RAW 264.7 cells induced by lipopolysaccharide (LPS). Co-treatment with magnolol significantly inhibited LPS-stimulated iNOS and COX-2 protein and gene expression.Western blot analysis and reporter assay showed that magnolol reduced translocation of the p50 and p65 subunit by reducing the degradation and phosphorylation of inhibitor jB (IjB), and subsequent transcriptional activity of NF-jB. We also found that magnolol blocked LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, Jun N-terminal kinase (JNK) 1/2 and phosphatidylinositiol 3-kinase (PI3 K)/Akt signaling but no p38 mitogen-activated protein kinase (MAPK). These results suggest that magnolol inhibits iNOS and COX-2 protein and gene expression by blocking the activation of NF-jB through interference with activation of PI3K/Akt and MAPK signaling. These findings suggest that magnolol may have potential to be developed into an effective anti-inflammatory agent.

Pterostilbene is an effective chemopreventive agent against multiple types of cancer cells. A novel pterostilbene derivative, ANK-199, was designed and synthesized by our group. Its antitumor activity and mechanism in cisplatin-resistant CAR human oral cancer cells were investigated in this study. Our results show that ANK-199 has an extremely low toxicity in normal oral cell lines. The formation of autophagic vacuoles and acidic vesicular organelles (AVOs) was observed in the ANK-199-treated CAR cells by monodansylcadaverine (MDC) and acridine orange (AO) staining, suggesting that ANK-199 is able to induce autophagic cell death in CAR cells. Neither DNA fragmentation nor DNA condensation was observed, which means that ANK-199-induced cell death is not triggered by apoptosis. In accordance with morphological observation, 3-MA, a specific inhibitor of PI3K kinase class III, can inhibit the autophagic vesicle formation induced by ANK-199. In addition, ANK-199 is also able to enhance the protein levels of autophagic proteins, Atg complex, beclin 1, PI3K class III and LC3-II, and mRNA expression of autophagic genes Atg7, Atg12, beclin 1 and LC3-II in the ANK-199-treated CAR cells. A molecular signaling pathway induced by ANK-199 was therefore summarized. Results presented in this study show that ANK-199 may become a novel therapeutic reagent for the treatment of oral cancer in the near future (patent pending).