Design, Synthesis and Biological Activity Testing of Library of Sphk1 Inhibitors
Shuangshuang Geng,
Haijiao Chen,
Yan Li,
Ying Li,
Jingxiang Pang,
Feipeng Zhang,
Zhiqiang Qu,
Mengjun Li,
Na Liu,
Qingqiang Yao,
Yanling Mu,
Bo Liu
Affiliations
Shuangshuang Geng
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
Haijiao Chen
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
Yan Li
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
Ying Li
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
Jingxiang Pang
Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
Feipeng Zhang
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
Zhiqiang Qu
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
Mengjun Li
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
Na Liu
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
Qingqiang Yao
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
Yanling Mu
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
Bo Liu
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
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.
