Correction: Non-peptide compounds from Kronopolites svenhedini (Verhoeff) and their antitumor and iNOS inhibitory activities.

[This corrects the article DOI: 10.3762/bjoc.19.59.].

Design, synthesis, and biological evaluation of thiazole/thiadiazole carboxamide scaffold-based derivatives as potential c-Met kinase inhibitors for cancer treatment.

As part of our continuous efforts to discover novel c-Met inhibitors as antitumor agents, four series of thiazole/thiadiazole carboxamide-derived analogues were designed, synthesised, and evaluated for the in vitro activity against c-Met and four human cancer cell lines. After five cycles of optimisation on structure-activity relationship, compound 51am was found to be the most promising inhibitor in both biochemical and cellular assays. Moreover, 51am exhibited potency against several c-Met mutants. Mechanistically, 51am not only induced cell cycle arrest and apoptosis in MKN-45 cells but also inhibited c-Met phosphorylation in the cell and cell-free systems. It also exhibited a good pharmacokinetic profile in BALB/c mice. Furthermore, the binding mode of 51am with both c-Met and VEGFR-2 provided novel insights for the discovery of selective c-Met inhibitors. Taken together, these results indicate that 51am could be an antitumor candidate meriting further development.

Non-peptide compounds from Kronopolites svenhedini (Verhoeff) and their antitumor and iNOS inhibitory activities.

Six new compounds, including a tetralone 1, two xanthones 2 and 3, a flavan derivative 4, and two nor-diterpenoids 7 and 8, accompanied by two known flavan derivatives 5 and 6 and a known olefine acid (9) were isolated from whole bodies of Kronopolites svenhedini (Verhoeff). The structures of the new compounds were determined by 1D and 2D nuclear magnetic resonance (NMR) and other spectroscopic methods, as well as computational methods. Selected compounds were evaluated for their biological properties against a mouse pancreatic cancer cell line and inhibitory effects on iNOS and COX-2 in RAW264.7 cells.

Dichotomous Roles of Programmed Cell Death 1 on HIV-Specific CXCR5+ and CXCR5- CD8+ T Cells during Chronic HIV Infection.

BACKGROUND: CXCR5+CD8+ T cells have been demonstrated to play an important role in the control of chronic viral replication; however, the relationship between CXCR5+CD8+ T cells, HIV disease progression, and programmed cell death 1 (PD-1) expression profile on CXCR5+CD8+ T cells during HIV infection remain poorly understood. METHODS: We enrolled a total of 101 HIV patients, including 62 typical progressors, 26 complete responders (CRs), and 13 immune non-responders (INRs). Flow cytometric analysis, immunohistochemical staining, and relative function (i.e., cytokine secretion and PD-1 blockade) assays were performed to analyze the properties of CXCR5+CD8+ T cells. RESULTS: HIV-specific CXCR5+CD8+ T cells in the peripheral blood and distribution of CXCR5+CD8+ T cells in the lymph node (LN) were negatively correlated with disease progression during chronic HIV infection. PD-1 was highly expressed on CXCR5+CD8+ T cells and positively associated with peripheral CD4+ T cell counts. Functionally, IFN-γ and TNF-α production of CXCR5+CD8+ T cells were reduced by PD-1 pathway blockade, but the production of IFN-γ and TNF-α from CXCR5-CD8+ T cells increased in response to TCR stimulation. Interestingly, PD-1 expression was constantly retained on CXCR5+CD8+ T cells while significantly decreased on CXCR5-CD8+ T cells after successful antiretroviral treatment in chronic HIV-infected patients. CONCLUSION: PD-1+CXCR5+CD8+ T cells are functional cytotoxic T cells during chronic HIV infection. PD-1+CXCR5+CD8+ T cells may represent a novel therapeutic strategy for the disease.

[The study on frequency distribution of regulatory T cells and its functional markers in peripheral blood of chronic hepatitis B].

OBJECTIVE: To explore the role of treg cells and its functional markers in pathogenesis of chronic hepatitis B, and the correlation with disease progression. METHODS: 20 cases of healthy control people,53 cases of chronic hepatitis B patients and 24 cases of liver cirrhosis patients were enrolled into the groups. Detecting the frequencies of CD4+ CD25+ Fox3+ cells, CD4+ CD25+ CD127(low) cells, CD39+ treg cells and CTLA-4+ treg cells in treg cells by flow cytometry. Clinical parameters were investigated in the same time. RESULTS: The frequencies of treg cells, CD4+ CD25+ CD127(low) cells and CD39+ treg cells were significant different among healthy control group, CHB group and LC group (P < 0.01). The frequencies of treg cells, CD4+ CD25+ CD127(low) cells and CD39+ treg cells were significantly different in moderate-severe CHB group compared with mild CHB group (P < 0.05, P < 0.05, P < 0.01). In CHB group the frequencies of CD4+ CD25+ Foxp3+ cells were positively correlated with ALT (r = 0. 289, P < 0.05) and AST (r = 0.302, P < 0.05), the frequencies of CD4+ CD25+ Foxp3+ cells had a significant positive correlation with the frequencies of CD4+ CD25+ CD127(low) cells (r = 0.478, P < 0.01). CONCLUSION: The frequencies of treg cells and its functional markers probably had a dynamic tendency in the process of chronic hepatitis B and were closely related with the change of liver function parameters. CD39+ treg cells may be a group of functional treg cells, which indicated that CD39 be a sensitive marker to react treg cells function. In some sense, CD4+ CD25+ CD127(low) cells frequency could represent treg cell frequency.