巴卡亭 III（贾斯帕碱 B）及其立体异构体抑制鞘氨醇激酶和非典型蛋白激酶 C。

Pachastrissamine (jaspine B) and its stereoisomers inhibit sphingosine kinases and atypical protein kinase C.

机构信息

Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.

出版信息

Bioorg Med Chem. 2011 Sep 15;19(18):5402-8. doi: 10.1016/j.bmc.2011.07.061. Epub 2011 Aug 4.

DOI:10.1016/j.bmc.2011.07.061

Abstract

Sphingosine kinases (SphKs) are oncogenic enzymes that regulate the critical balance between ceramide and sphingosine-1-phosphate. Much effort has been dedicated to develop inhibitors against these enzymes. Naturally occurring pachastrissamine (jaspine B) and all its stereoisomers were prepared and evaluated for their inhibitory effects against SphKs. All eight stereoisomers exhibited moderate to potent inhibitory activity against SphK1 and SphK2. Inhibitory effects were profiled against protein kinase C (PKC) isoforms by in vitro experiments. Atypical PKCs (PKCζ and PKCι) were inhibited by several pachastrissamine stereoisomers. The improved activity over N,N-dimethylsphingosine suggests that the cyclic scaffold in pachastrissamines facilitates potential favorable interactions with SphKs and PKCs.

摘要

鞘氨醇激酶（SphKs）是致癌酶，可调节神经酰胺和鞘氨醇-1-磷酸之间的关键平衡。人们致力于开发针对这些酶的抑制剂。天然存在的帕夏斯他汀（jaspine B）及其所有立体异构体都被制备并评估了它们对 SphKs 的抑制作用。所有八个立体异构体对 SphK1 和 SphK2 均表现出中等至强的抑制活性。通过体外实验对蛋白激酶 C（PKC）同工型进行了抑制作用分析。几种帕夏斯他汀立体异构体抑制非典型 PKC（PKCζ和 PKCι）。与 N，N-二甲基鞘氨醇相比，活性提高表明帕夏斯他汀中的环状支架有利于与 SphKs 和 PKCs 产生潜在的有利相互作用。