Background: Sphingolipids, even in extremely low doses, regulate various physiological functions. Particularly, immune and cancer cells might be controlled by changes in the sphingosine- 1-phosphate (S1P) levels, and S1P has been studied for a long time as a major target for new drug development. Sphingosine kinase (SK) phosphorylates sphingosine to produce S1P. An increase in the S1P levels promotes the growth of cancer cells. SK has 2 isoforms, SK1 and SK2, both of which are involved in the growth of cancer cells.

Objective: PF-543 has been developed as an SK1 inhibitor and has a non-lipid structure that differs from those of general SK inhibitors. While PF-543 has a potent SK1 inhibitory effect, and has low anticancer activity in some types of cancer cells. Therefore, the development of other PF-543 derivatives is needed.

Methods: We designed a structurally simplified derivative of PF-543. To primarily demonstrate that the designed structure was biologically active, 8 derivatives were synthesized by a 2-step method using the commercial starting material, and their biological activities were evaluated.

Results: The SK1-inhibitory effects of the synthesized derivatives were not higher than that of PF- 543. However, the anticancer activity and apoptotic effect of the derivatives were similar to those of PF-543, despite their fabrication from a simple modification of the PF-543 structure. In a docking study, the derivatives were found to bind SK1 in a form similar to PF-543.

Conclusion: Our analogs, which are similar to PF-543, showed comparable anticancer activity, indicating that the synthesized derivatives are structurally more efficient for anticancer activity than PF-543. Therefore, our study provides important information that may be useful for developing new anticancer substances that target SK1.

背景：鞘脂即使在极低剂量下也能调节各种生理功能。特别是，免疫细胞和癌细胞可能受鞘氨醇-1-磷酸酯（S1P）水平变化的控制，并且作为一种新药物开发的主要目标，人们已经对S1P进行了长期的研究。鞘氨醇激酶（SK）使鞘氨醇磷酸化以产生S1P。S1P水平的增加促进癌细胞的生长。SK有两个同工型，SK1和SK2，它们都参与癌细胞的生长。

目的：PF-543已开发为SK1抑制剂，其非脂质结构不同于一般的SK抑制剂。PF-543具有有效的SK1抑制作用，并且在某些类型的癌细胞中具有较低的抗癌活性。因此，需要开发其他PF-543衍生物。

方法：我们设计了结构简化的PF-543衍生物。为了初步证明所设计的结构具有生物活性，使用市售起始原料通过两步法合成了8种衍生物，并对其生物活性进行了评估。

结果：合成衍生物的SK1抑制作用不高于PF-543。但是，尽管这些衍生物是通过对PF-543的简单修饰而制得的，但其抗癌活性和凋亡作用与PF-543相似。 PF-543结构。在对接研究中，发现衍生物以类似于PF-543的形式结合SK1。

结论：我们的类似物与PF-543相似，显示出可比的抗癌活性，表明合成的衍生物在结构上比PF-543更有效。因此，我们的研究提供了重要的信息，这些信息可能对开发针对SK1的新型抗癌物质有用。