Design, Synthesis and Biological Activity Testing of Library of Sphk1 Inhibitors
oleh: Shuangshuang Geng, Haijiao Chen, Yan Li, Ying Li, Jingxiang Pang, Feipeng Zhang, Zhiqiang Qu, Mengjun Li, Na Liu, Qingqiang Yao, Yanling Mu, Bo Liu
| Format: | Article |
|---|---|
| Diterbitkan: | MDPI AG 2022-03-01 |
Deskripsi
Our team discovered a moderate SphK1 inhibitor, <b>SAMS10</b> (IC<sub>50</sub> = 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 <b>SAMS10</b>. A total of 50 new compounds were synthesized. Among these compounds, the most potent compound, named <b>CHJ04022Rb,</b> has significant anticancer activity in melanoma A375 cell line (IC<sub>50</sub> = 2.95 μM). Further underlying mechanism studies indicated that <b>CHJ04022R</b> 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 <b>CHJ04022R</b> exhibited good safety in vivo. Additionally, it showed a dose-dependent inhibitory effect on the growth of xenograft tumor in nude mice. Therefore, <b>CHJ04022R</b> may be a potential candidate for the treatment of melanoma.