The PF-543 is known as a potent and selective inhibitor of sphingosine kinase (SK) 1 amongst all the SK inhibitors known to date. In a recently reported study by Pfizer on the synthesis of PF-543 derivatives and the SK inhibitory effects, the introduction of propyl moiety into sulfonyl group of PF-543 in the case of 26b revealed an excellent result of 1.7 nM of IC50 of SK1, suggesting the potential substitution of chain structure for benzenesulfonyl structure. In the present work, we aimed for identification of antitumor activity and inhibitory effects of PF-543 derivative containing aliphatic long chain (similar to known SK inhibitors) on SK1. The synthesized compound 2 exhibited an inhibitory effect on SK1 in a manner similar to that of PF-543; the PF-543 derivative manifested similar antitumor activity on HT29, HCT116 (colorectal cancer cell line), and AGS (gastric cancer cell line) cells. Also, from the docking study conducted with PF-543 and compound 2, it was apparent that the aliphatic chain in compound 2 could probably replace benzenesulfonyl structure of PF-543.

中文翻译：

---

含脂肪侧链的PF-543衍生物的合成及生物学评价。

在迄今为止已知的所有SK抑制剂中，PF-543被认为是鞘氨醇激酶（SK）1的有效和选择性抑制剂。辉瑞公司最近报道的有关PF-543衍生物的合成和SK抑制作用的研究表明，在26b的情况下，将丙基部分引入PF-543的磺酰基中显示了1.7 nM的SK1 IC50优异结果，暗示了链结构可能被苯磺酰基结构取代。在本工作中，我们旨在鉴定含脂族长链的PF-543衍生物（类似于已知的SK抑制剂）的抗肿瘤活性和抑制作用。合成的化合物2以类似于PF-543的方式对SK1表现出抑制作用。PF-543衍生物对HT29具有相似的抗肿瘤活性，HCT116（结直肠癌细胞系）和AGS（胃癌细胞系）细胞。同样，从对PF-543和化合物2的对接研究中可以明显看出，化合物2中的脂族链可能会取代PF-543的苯磺酰基结构。