Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure–activity relationship study of 4-epi-jaspine B
作者:Hiroaki Ohno、Maho Honda、Naoka Hamada、Jun Miyagaki、Akira Iwata、Kazuhiro Otsuki、Toru Maruyama、Shinya Nakamura、Isao Nakanishi、Shinsuke Inuki、Nobutaka Fujii、Shinya Oishi
DOI:10.1016/j.bmc.2017.03.059
日期:2017.6
We recently reported that 4-epi-jaspine B exhibits potent inhibitory activity towards sphingosine kinases (SphKs). In this study, we investigated the effects of modifying the 2-alkyl group, as well as the functional groups on the THF ring of 4-epi-jaspine B using a diversity-oriented synthesis approach based on a late-stage cross metathesis reaction. The introduction of a p-phenylene tether to the
最近,我们报道了4-epi-jaspine B对鞘氨醇激酶(SphKs)表现出强大的抑制活性。在这项研究中,我们使用基于后期交叉复分解反应的面向多样性的合成方法,研究了修饰2-表山s B的2-烷基基团以及THF环上官能团的作用。在大多数情况下,将对亚苯基系链引入烷基是有利的,而用氧原子取代碳原子会导致抑制活性的降低。此外,在末端引入大分子烷基导致该系列对SphKs的抑制活性与4-eps-jaspine B相比略有增加(化合物13对SphK1和SphK2的Q值分别为0.2和0.4,分别)。根据这项研究,我们确定了两种同工型选择性抑制剂,包括间亚苯基衍生物4 [IC50(SphK1)≥30μM;IC50(SphK2)=2.2μM]和甲基醚衍生物22 [IC50(SphK1)=4.0μM; IC50(SphK2)≥30μM]。