Pachastrissamine (jaspine B) and its stereoisomers inhibit sphingosine kinases and atypical protein kinase C
Pachastrissamine (jaspine B) and its stereoisomers inhibit sphingosine kinases and atypical protein kinase C
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DOI：
10.1016/j.bmc.2011.07.061
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发表时间：
2011-09-15
影响因子：
3.5
通讯作者：
Fujii, Nobutaka
中科院分区：
文献类型：
--
作者：
Yoshimitsu, Yuji;Oishi, Shinya;Fujii, Nobutaka
鞘氨醇激酶（SphKs）是调节神经酰胺和鞘氨醇-1-磷酸之间的临界平衡的致癌酶。人们一直致力于开发针对这些酶的抑制剂。制备了天然茉莉胺（jaspine B）及其所有立体异构体，并评价了它们对SphKs的抑制作用。所有8种立体异构体对SphK1和SphK2均表现出中强抑制活性。通过体外实验分析了其对蛋白激酶C （PKC）异构体的抑制作用。非典型PKCs （PKC zeta和PKC iota）被几种pachastrisamine立体异构体抑制。对N，N-二甲基鞘氨醇活性的提高表明，环支架在pachastrissamines中促进了与SphKs和PKCs潜在的有利相互作用。(C) 2011 Elsevier Ltd.版权所有。
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 (PKC zeta and PKC iota) 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. (C) 2011 Elsevier Ltd. All rights reserved.