L-ascorbyl 6-palmitate as lead compound targeting SphK1: an in silico and in vitro investigation
L-ascorbyl 6-palmitate as lead compound targeting SphK1: an in silico and in vitro investigation
复制标题
L-抗坏血酸 6-棕榈酸酯作为靶向 SphK1 的先导化合物：计算机和体外研究
DOI：
10.1177/17475198211001819
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发表时间：
2021-03-28
影响因子：
1.4
通讯作者：
Liu, Bo
中科院分区：
文献类型：
--
作者：
Chen, HaiJiao;Yang, Xinmei;Liu, Bo
鞘氨酸激酶（SphKs）是一类脂质激酶，作为肿瘤中重要的限速酶而受到广泛关注。抑制SphK1的活性可导致抗癌作用。在此，我们描述了通过计算机辅助药物设计发现的一种新的SphK1抑制剂抗坏血酸棕榈酸酯的发现过程和生物学特性。生化实验表明，抗坏血酸棕榈酸酯对SphK1具有较强的抑制作用，IC50值为6.4 μM。MTT实验表明，抗坏血酸棕榈酸酯对U87、A549、22RV1和A375细胞系具有抗癌作用。其中，抗坏血酸棕榈酸酯对22RV1细胞株具有显著的抑制活性，IC50值为41.57 μM。为探究其构效关系，合成了四种抗坏血酸棕榈酸衍生物，并进行了激酶活性测试。抗坏血酸棕榈酸酯对SphK1的显著作用及其已知的无毒性表明，抗坏血酸棕榈酸酯可能是开发有效的SphK1抗癌抑制剂的先导化合物。
Sphingosine kinases (SphKs) are a class of lipid kinases, that have received extensive attention as important rate-limiting enzyme in tumor. Inhibition of the activity of SphK1 can lead to an anticancer effect. Herein, we describe the discovery process and biological characteristics of a new SphK1 inhibitor, ascorbyl palmitate, discovered through computer-aided drug design. Biochemical experiments show that ascorbyl palmitate has a strong inhibitory effect on SphK1, with an IC50 value of 6.4 μM. The MTT experiment showed that ascorbyl palmitate had anti-cancer effects toward the U87, A549, 22RV1, and A375 cell lines. Among them, ascorbyl palmitate has prominent inhibitory activity against the 22RV1 cell line, with an IC50 value of 41.57 μM. To explore the structure–activity relationship, four ascorbyl palmitate derivatives were synthesized and tested for kinase activity. The outstanding effect of ascorbyl palmitate toward SphK1 and its known non-toxicity suggest that ascorbyl palmitate may be a lead compound for the development of effective SphK1 anti-cancer inhibitors.