期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 20, 期 14, 页码 4226-4236出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.05.055
关键词
1,3,4-Oxadiazole derivatives; PI3K gamma inhibitor; Immunosuppressive activities; ELISA; Molecular docking
资金
- National Natural Science Foundation of China [J1103512]
In present study, a series of novel 1,3,4-oxadiazole derivatives have been designed, synthesized and purified. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of H-1 NMR, ESI-MS and elemental analyses. Besides, we evaluated their immunosuppressive activity. Most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, the bioassay results demonstrated that compounds 5c, 5n, 5p, 5o, 6f and 6g exhibited immunosuppressive activities with IC50 concentration range from 1.25 mu M to 7.60 mu M against the T cells, and the IC50 of positive control (csa) is 2.12 mu M. Moreover, all the title compounds were assayed for PI3K/AKT signaling pathway inhibition using the ELISA assay. We examined the compounds with potent inhibitory activities against IL-1, IL-6 and IL-10 released in ConA-simulated mouse lymph node cells. The results showed compounds 5o and 6f displayed the most potential biological activity against T cells (IC50 = 1.25 mu M and 4.75 mu M for T cells). The preliminary mechanism of compound 5o inhibition effects was also detected by flow cytometry (FCM). The results of apoptosis and ELISA assay demonstrated that the immunosuppressive activity of compounds 5o and 6f against T cells may be mediated by the inhibition of PI3K gamma/AKT signaling pathway. Molecular docking was performed to position compounds 5o and 6f into PI3K gamma binding site in order to indicate the potential target. (C) 2012 Elsevier Ltd. All rights reserved.
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