Tongchao Liu

Discovery and Biological Evaluation of a Series of Pyrrolo[2,3-b]pyrazines as Novel FGFR Inhibitors

Abnormality of fibroblast growth factor receptor (FGFR)-mediated signaling pathways were frequently found in various human malignancies, making FGFRs hot targets for cancer treatment. To address the consistent need for a new chemotype of FGFR inhibitors, here, we started with a hit structure identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and conducted a chemical optimization. After exploring three parts of the hit compound, we finally discovered a new series of pyrrolo[2,3-b]pyrazine FGFR inhibitors, which contain a novel scaffold and unique molecular shape. We believe that our findings can help others to further develop selective FGFR inhibitors.

Discovery of a new series of imidazo[1,2-a]pyridine compounds as selective c-Met inhibitors

Aim:Aberrant c-Met activation plays a critical role in cancer formation, progression and dissemination, as well as in development of resistance to anticancer drugs. Therefore, c-Met has emerged as an attractive target for cancer therapy. The aim of this study was to develop new c-Met inhibitors and elaborate the structure-activity relationships of identified inhibitors.Methods:Based on the predicted binding modes of Compounds 5 and 14 in docking studies, a new series of c-Met inhibitor-harboring 3-((1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)imidazo[1,2-a]pyridine scaffolds was discovered. Potent inhibitors were identified through extensive optimizations combined with enzymatic and cellular assays. A promising compound was further investigated in regard to its selectivity, its effects on c-Met signaling, cell proliferation and cell scattering in vitro.Results:The most potent Compound 31 inhibited c-Met kinase activity with an IC50 value of 12.8 nmol/L, which was >78-fold higher than those of a panel of 16 different tyrosine kinases. Compound 31 (8, 40, 200 nmol/L) dose-dependently inhibited the phosphorylation of c-Met and its key downstream Akt and ERK signaling cascades in c-Met aberrant human EBC-1 cancer cells. In 12 human cancer cell lines harboring different background levels of c-Met expression/activation, Compound 31 potently inhibited c-Met-driven cell proliferation. Furthermore, Compound 31 dose-dependently impaired c-Met-mediated cell scattering of MDCK cells.Conclusion:This series of c-Met inhibitors is a promising lead for development of novel anticancer drugs.

Influence of work-family conflict on job involvement and organizational commitment: The moderating effect of perceived supervisor support and the mediating effect of job satisfaction

The study aims to explore the influence of work-family conflicts on job involvement and organizational commitment, we also investigated the moderating effect of perceived supervisor support and the mediating effect of job satisfaction. 558 employees from small and middle size enterprise participated in our research, they came from 19 organizations including Eight different regions such as Beijing, Shenyang and Hangzhou. By hierarchical regression and bootstrapping, our hypotheses have been supported. Results showed that perceived supervisor support moderated the effect of work-family conflicts on job satisfaction. When perceived supervisor support is low, work-family conflicts negatively predicted job satisfaction; however, when perceived supervisor support is high, work-family conflicts had no effect on job satisfaction. We also supported the moderated mediation model, job satisfaction mediated the interaction of work-family conflicts and perceived supervisor support on job involvement and organizational commitment.

Efficient syntheses of alpha- and beta-C-nucleosides and the origin of anomeric selectivity

C-Nucleosides constitute a valuable class of compounds in biological and medicinal chemistry studies. We report herein a new and efficient synthesis of both alpha- and beta-C-nucleosides with high anomeric selectivity from N6-Boc protected purine analogues. The synthetic approach features a carefully designed lithiation and silane reduction sequence. The anomeric stereochemistry outcome is dictated by the protecting group of sugar lactones. Computational studies suggest that previously neglected interactions between partially positively-charged silane and the substitutions on a sugar moiety play important roles in the anomeric selectivity of silane-mediated C-nucleoside synthesis.

A one-pot synthesis of omarigliptin and its analogues through stabilized beta-amino ketone intermediate

ABSTRACT We have discovered a unique stabilization condition for beta-amino ketone 7. With compound 7 as an unprecedented intermediate, omarigliptin 1 could be prepared in a highly efficient one-pot procedure with good yield. Also with this intermediate 7, some analogues of omarigliptin 1 were readily prepared for the first time. GRAPHICAL ABSTRACT

The impact of work-family interface on turnover intention of IT R&D personnel: A mediator role of psychological contract

Taking the group of IT R&D personnel as the research subject, we investigated 267 employees through the questionnaire of work-family conflict, work-family promotion, psychological contract and turnover intention. The results showed: 1) Work-family conflict negatively affects psychological contract, and positively affects turnover intention; 2) Work-family promotion positively affects psychological contract, and negatively affects turnover intention; 3) Psychological contract partly mediates the effect of work-family conflict and promotion on turnover intention. This study filled the gaps of theoretical research, and provided realistic suggestions to the enterprise how to reduce turnover rate.