Synthesis and identification of quinoline derivatives as topoisomerase I inhibitors with potent antipsoriasis activity in an animal model.

Psoriasis is a chronic inflammatory and immune-mediated skin disease. Although certain agents have shown clinical success in treating psoriasis, development of safe and effective strategies for the treatment of this condition remains important. Research suggests that DNA topoisomerase I (Topo I) inhibitors may have potent psoriasis-ameliorating effects. Here, 25 quinoline derivatives were synthesized and identified as Topo I inhibitors. These compounds inhibited the 12-O-tetradecanoylphorbol-13-acetate-induced mouse ear inflammation. The most potent analogs, 5i and 5l, suppressed the expression of inflammatory cytokines in lipopolysaccharide-stimulated HaCaT cells. Additionally, the lead compounds significantly improved imiquimod-induced psoriasis-like inflammation in mice. Moreover, the expression levels of cytokines and inflammatory mediators, such as interleukin (IL)-17A, IL-22, IL-23, nuclear factor-κB subunit p65, tumor necrosis factor-α, and interferon-γ, were dramatically inhibited in the dorsal skin of 5i- and 5l-treated mice. These findings indicate that the inhibition of Topo I activity may potentially be an effective strategy for psoriasis treatment.

Anti-inflammatory effects of paeoniflorin from Paeonia lactiflora Pall. on human corneal epithelial cells and a mouse model of dry eye disease.

Dry eye disease (DED) is characterized by increased osmolality of tears due to a lack of production or increased evaporation of tears. Hyperosmolarity is involved in DED pathogenesis, which damages ocular surface cells and leads to inflammation of the ocular surface. We investigated the anti-inflammatory effect of paeoniflorin (PF) from Paeonia lactiflora Pall. on human corneal epithelial (HCE) cells and its molecular mechanisms, and its therapeutic effects on a mouse model of experimental dry eye (EDE). HCE cells were treated with PF-1 (PF prepared in vitro; 0.01%, 0.1% and 1.0%). Protein production/activity was determined by Western blotting, RT-PCR and immunofluorescent staining. Meanwhile, eye drops containing 0.01%, 0.1% and 1.0% of PF-2 (PF prepared in vivo) were applied to the EDE, and the tear volume, corneal fluorescein-staining score, detachment of the corneal epithelium, and immunohistochemical staining were measured after 28 days of treatment. PF reduced expression of proinflammatory factors such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α in HCE cells, and significantly improved dry-eye signs, including tear volume, desquamation of the corneal epithelium and ocular surface inflammation in mice treated with 1.0% PF-2. Further study showed that PF improved EDE by inhibiting mitogen-activated protein kinase (MAPK), phosphorylated (p)-c-Jun N-terminal kinase (JNK) and pp-38, and nuclear factor kappa B (NF-κB) signaling pathways. These data suggest that PF can improve dry-eye symptoms and reduce expression of proinflammatory mediators. Hence, eye drops containing PF could be used as an adjunctive treatment for DED.

Synthesis of carbazole derivatives containing chalcone analogs as non-intercalative topoisomerase II catalytic inhibitors and apoptosis inducers.

Novel topoisomerase II (Topo II) inhibitors have gained considerable interest for the development of anticancer agents. In this study, a series of carbazole derivatives containing chalcone analogs (CDCAs) were synthesized and investigated for their Topo II inhibition and cytotoxic activities. The results from Topo II mediated DNA relaxation assay showed that CDCAs could significantly inhibit the activity of Topo II, and the structure-activity relationship indicated the halogen substituent in phenyl ring play an important role in the activity. Further mechanism studies revealed that CDCAs function as non-intercalative Topo II catalytic inhibitors. Moreover, some CDCAs showed micromolar cytotoxic activities. The most potent compound 3h exhibited notable growth inhibition against four human cancer cell lines. Flow cytometric analysis revealed that compounds 3d and 3h arrested the HL-60 cells in sub G1 phase by induction of apoptosis. It was further confirmed by Annexin-V-FITC binding assay. Western blot analysis revealed that compound 3h induces apoptosis likely through the activation of caspase proteins.

Variation in Essential Oil and Bioactive Compounds of Curcuma kwangsiensis Collected from Natural Habitats.

The chemical compositions of essential oils (EOs) extracted from Curcuma kwangsiensis rhizomes collected from six natural habitats in P. R. China were evaluated using gas chromatography/mass spectrometry (GC/MS). Fifty-seven components were identified from the six EOs, and their main constituents were 8,9-dehydro-9-formyl-cycloisolongifolene (2.37 - 42.59%), germacrone (6.53 - 22.20%), and l-camphor (0.19 - 6.12%). The six EOs exhibited different DPPH radical-scavenging activities (IC50 , 2.24 - 31.03 µg/ml), with the activity of most of EOs being much higher than that of Trolox C (IC50 , 10.49 µg/ml) and BHT (IC50 , 54.13 µg/ml). Most EOs had potent antimicrobial effects against the tested bacteria and fungus. They also exhibited cytotoxicity against B16 (IC50 , 4.44 - 147.4 µg/ml) and LNCaP cells (IC50 , 73.94 - 429.25 µg/ml). The EOs showed excellent anti-inflammatory action by significantly downregulating expression of pro-inflammatory cytokines, cyclooxygenase-2, and tumor necrosis factor-α. This study provides insight into the interrelation among growth location, phytoconstituents, and bioactivities, and the results indicate the potential of C. kwangsiensis as natural nutrients, medicines, and others additives.