Design,Synthesis and Biological Activity Testing of Library of Sphk1 Inhibitors |
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| Authors: | Shuangshuang Geng Haijiao Chen Yan Li Ying Li Jingxiang Pang Feipeng Zhang Zhiqiang Qu Mengjun Li Na Liu Qingqiang Yao Yanling Mu Bo Liu |
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| Institution: | 1.Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China; (S.G.); (H.C.); (Y.L.); (Y.L.); (F.Z.); (Z.Q.); (M.L.); (N.L.); (Q.Y.);2.Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China; |
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| Abstract: | Our team discovered a moderate SphK1 inhibitor, SAMS10 (IC50 = 9.8 μM), which was screened by computer-assisted screening. In this study, we developed a series of novel diaryl derivatives with improved antiproliferative activities by modifying the structure of the lead compound SAMS10. A total of 50 new compounds were synthesized. Among these compounds, the most potent compound, named CHJ04022Rb, has significant anticancer activity in melanoma A375 cell line (IC50 = 2.95 μM). Further underlying mechanism studies indicated that CHJ04022R exhibited inhibition effect against PI3K/NF-κB signaling pathways, inhibited the migration of A375 cells, promoted apoptosis and exerted antiproliferative effect by inducing G2/M phase arrest in A375 cells. Furthermore, acute toxicity experiment indicated CHJ04022R exhibited good safety in vivo. Additionally, it showed a dose-dependent inhibitory effect on the growth of xenograft tumor in nude mice. Therefore, CHJ04022R may be a potential candidate for the treatment of melanoma. |
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| Keywords: | SphK1 inhibitor melanoma PI3K/NF-κ B signaling pathway xenograft tumor |
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