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1. chinaXiv:201605.01195 [pdf]

Discovery and structural optimization of 1-phenyl-3-(1-phenylethyl)urea derivatives as novel inhibitors of CRAC channel

Zhang, Hai-zhen; Chen, Hua-yan; Nan, Fa-jun; Xu, Xiao-lan; Ali, Sher; Wang, Dan; Yu, Jun-wei; Xu, Tao
Subjects: Biology >> Biophysics

Aim: Ca2+-release-activated Ca2+ (CRAC) channel, a subfamily of store-operated channels, is formed by calcium release-activated calcium modulator 1 (ORAI1), and gated by stromal interaction molecule 1 (STIM1). CRAC channel may be a novel target for the treatment of immune disorders and allergy. The aim of this study was to identify novel small molecule CRAC channel inhibitors. Methods: HEK293 cells stably co-expressing both ORAI1 and STIM1 were used for high-throughput screening. A hit, 1-phenyl-3-(1-phenylethyl)urea, was identified that inhibited CRAC channels by targeting ORAI1. Five series of its derivatives were designed and synthesized, and their primary structure-activity relationships (SARs) were analyzed. All derivatives were assessed for their effects on Ca2+ influx through CRAC channels on HEK293 cells, cytotoxicity in Jurkat cells, and IL-2 production in Jurkat cells expressing ORAI1-SS-eGFP. Results: A total of 19 hits were discovered in libraries containing 32 000 compounds using the high-throughput screening. 1-Phenyl-3-(1-phenylethyl) urea inhibited Ca2+ influx with IC50 of 3.25 +/- 0.17 mu mol/L. SAR study on its derivatives showed that the alkyl substituent on the a-position of the left-side benzylic amine (R1) was essential for Ca2+ influx inhibition and that the S-configuration was better than the R-configuration. The derivatives in which the right-side R3 was substituted by an electron-donating group showed more potent inhibitory activity than those that were substituted by electron-withdrawing groups. Furthermore, the free N-H of urea was not necessary to maintain the high potency of Ca2+ influx inhibition. The N, N'-disubstituted or N'-substituted derivatives showed relatively low cytotoxicity but maintained the ability to inhibit IL-2 production. Among them, compound 5b showed an improved inhibition of IL-2 production and low cytotoxicity. Conclusion: 1-Phenyl-3-(1-phenylethyl) urea is a novel CRAC channel inhibitor that specifically targets ORAI1. This study provides a new chemical scaffold for design and development of CRAC channel inhibitors with improved Ca2+ influx inhibition, immune inhibition and low cytotoxicity.

submitted time 2016-05-11 Hits662Downloads353 Comment 0

2. chinaXiv:201605.00278 [pdf]


Liu, Yalong; Xu, Ke; Zhang, Youguang; Wang, Lei; Xu, Xiyu; Chen, Hua
Subjects: Geosciences >> Space Physics

This paper is aimed to assess the accuracy of HY-2A altimetry system. To further improve the accuracy and performance of HY-2A observed SSHs, several new treatments including 4 parameters maximum likelihood estimation (MLE4) retracking for Ku and C band, non-parameter sea state bias (NPSSB) model, and reprocessed dual-frequency altimeter ionospheric correction are included. The evaluation from dual-crossover comparison of the fully reprocessed level-2 sensor geophysical dataset records (SGDRs) data suggests that the algorithm and model improvements mentioned above give rise to remarkable promotion to the accuracy of the forthcoming version GDRs. In this study we conclude that the standard deviation of 5.79 cm is achieved from crossover comparison between HY-2A and Jason-2 sea surface height (SSHs), suggesting a promising situation of HY-2A altimetry datasets.

submitted time 2016-05-03 Hits984Downloads476 Comment 0

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