Design, Synthesis and Biological Activity Testing of Library of Sphk1 Inhibitors.
Design, Synthesis and Biological Activity Testing of Library of Sphk1 Inhibitors.
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Sphk1抑制剂文库的设计、合成及生物活性测试
DOI：
10.3390/molecules27062020
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发表时间：
2022-03-21
期刊：
影响因子：
--
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Geng S;Chen H;Li Y;Li Y;Pang J;Zhang F;Qu Z;Li M;Liu N;Yao Q;Mu Y;Liu B
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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