Design, synthesis and activity as acid cerarnidase inhibitors of 2-oxooctanoyl and N-oleoylethanolamine analogues
Design, synthesis and activity as acid cerarnidase inhibitors of 2-oxooctanoyl and N-oleoylethanolamine analogues
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DOI：
10.1016/j.chemphyslip.2006.07.001
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发表时间：
2006-10-01
影响因子：
3.4
通讯作者：
Fabrias, Gemma
中科院分区：
文献类型：
--
作者：
Grijalvo, Santiago;Bedia, Carmen;Fabrias, Gemma
本文报道了新型N-酰基乙醇胺的合成及其作为aCD酶抑制剂的应用。所述化合物是鞘氨醇类似物的2-氧代辛酰胺或油酰胺，其特征在于3-羟基-4，5-十六碳烯基尾被醚或硫醚部分取代。看来，在2-氧代辛酰胺家族中，鞘氨醇分子的C3-OH基团是体外和培养细胞中抑制所需的。此外，尽管（E）-4双键对于抑制活性不是必需的，但（E）构型是必需的，因为具有（Z）-4不饱和度的类似物不具有抑制性。没有油酰胺在体外抑制α CD酶。相反地，除了N-油酰乙醇胺及其具有S-癸基和S-十六烷基取代基的类似物之外，所有合成的油酰胺都抑制培养细胞中的aCD酶，尽管效力相对较低。我们的结论是，新的aCD酶抑制剂可以从N-酰化的鞘氨醇碱与缺电子酰基。相反，N-油酰鞘氨醇主链的化学修饰似乎没有提供获得α CD酶抑制剂的适当策略。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
The synthesis of novel N-acylethanolamines and their use as inhibitors of the aCDase is reported here. The compounds are either 2-oxooctanamides or oleamides of sphingosine analogs featuring a 3-hydroxy-4,5-hexadecenyl tail replaced by ether or thioether moieties. It appears that, within the 2-oxooctanamide family, the C3-OH group of the sphingosine molecule is required for inhibition both in vitro and in cultured cells. Furthermore, although the (E)-4 double bond is not essential for inhibitory activity, the (E) configuration is required, since the analogue with a (Z)-4 unsaturation was not inhibitory. None of the oleamides inhibited the aCDase in vitro. Conversely, with the exception of N-oleoylethanolamine and its analogs with S-decyl and S-hexadecyl substituents, all the synthesized oleamides inhibited the aCDase in cultured cells, although with a relatively low potency. We conclude that novel aCDase inhibitors can evolve from N-acylation of sphingoid bases with electron deficient-acyl groups. In contrast, chemical modification of the N-oleoylsphingosine backbone does not seem to offer an appropriate strategy to obtain aCDase inhibitors. (c) 2006 Elsevier Ireland Ltd. All rights reserved.