Dali Yin

Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-dimethylaminomethyl)phenyl)quinoline Derived Antitubercular Lead Compounds

Bedaquiline (BDQ) is a novel and highly potent last‐line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo‐structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compounds structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub‐microgram per mL concentrations against both sensitive and multidrug‐resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC‐ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower‐cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non‐ATP synthase related targets.

A Morphological identification cell cytotoxicity assay using cytoplasm-localized fluorescent probe (CLFP) to distinguish living and dead cells

Cell cytotoxicity assays include cell activity assays and morphological identification assays. Currently, all frequently used cytotoxicity assays belong to cell activity assays but suffer from detection limitations. Morphological identification of cell death remains as the gold standard, although the method is difficult to scale up. At present there is no generally accepted morphological identification based cell cytotoxicity assay. In this study, we applied previous developed cell cytoplasm-localized fluorescent probe (CLFP) to display cell morphologies. Under fluorescence microscopy, the fluorescence morphology and intensity of living cells are distinct from dead cells. Based on these characters we extracted the images of living cells from series of samples via computational analysis. Thus, a novel cell morphological identification cytotoxicity assay (CLFP assay) is developed. The performance of the CLFP assay was similar to cell activity assay (MTT assay), but the accuracy of the CLFP assay was superior when measuring the cytotoxicity of active compounds.

N′-[(3-[benzyloxy]benzylidene]-3,4,5-trihydroxybenzohydrazide (1) protects mice against colitis induced by dextran sulfate sodium through inhibiting NFκB/IL-6/STAT3 pathway

IBD has attracted much attention for its negative influence on the quality of life and increased risk of colorectal cancer. In this study, we discovered the inhibitory activity of the polyphenol compound (1) in DSS induced colitis in mice by targeting NFκB/IL-6/STAT3 pathway. This compound effectively protected against body weight loss and colon length shortening induced by DSS. Additionally, 1 inhibited DSS induced damage in colon, notably decreasing the severity of inflammation, the extent of inflammation, crypt damage and percent involvement. The production of inflammatory mediators of IL-6 and COX-2 was also significantly attenuated when treated with 1. It may be attributed to inhibiting NFκB signaling. Moreover, this polyphenol suppressed p-STAT3 production as well as its downstream proteins response for apoptosis, such as Bcl-2 and Bax. In summary, the study not only afforded our understanding involved in colitis, but also provided the possible therapy for human with IBD.

Identification and Structure–Activity Relationship (SAR) of potent and selective oxadiazole-based agonists of sphingosine-1-phosphate receptor (S1P1)

Agonism of S1P1 receptor has been proven to be responsible for peripheral blood lymphopenia and elicts the identification of various S1P1 modulators. In this paper we described a series of oxadiazole-based S1P1 direct-acting agonists disubstituted on terminal benzene ring, with high potency for S1P1 receptor and favorable selectivity against S1P3 receptor. In addition, two representative agents named 16-3b and 16-3g demonstrated impressive efficacy in lymphocyte reduction along with reduced effect on heart rate when orally administered. Furthermore, these compounds have been shown to possess desired pharmacokinetic (PK) and physicochemical profiles. The binding mode between 16-3b and the activated S1P1 model was also studied.

Quantitative Evaluation of in Vivo Target Efficacy of Anti-tumor Agents via an Immunofluorescence and EdU Labeling Strategy

Current methods used to evaluate in vivo target efficacy of selected compound include western blot to semi-quantitatively analyze protein expression. However, problems arise as it is difficult to compare in vivo target efficacy of anti-tumor agents with the same mode of action. It is therefore desirable to develop a protocol that can quantitatively display in vivo target efficacy while also providing other useful information. In this study EdU labeling was used to mark out the proliferating area. The tumor tissue was accordingly divided into proliferating and non-proliferating areas. Fifteen tumor related proteins were stained by immunofluorescence and were found to express in either the proliferating or non-proliferating areas. This allows the quantitative analysis of protein expressions within the precise area. With simple image analysis, our method gave precise percent changes of protein expression and cell proliferation between the drugs treated group and the control group. Additional information, such as, the status of protein expression can also be obtained. This method exhibits high sensitivity, and provides a quantitative approach for in vivo evaluation of target efficacy.