Rajan Roshini, Wallimann Kurt, Vasella Andrea, Pace Deborah, Genazzani Armando A, Canonico Pier Luigi, Condorelli Fabrizio
Laboratorium für Organische Chemie, ETH-Hönggerberg, Wolfgang Pauli-Strasse 10, CH-8093 Zürich.
Chem Biodivers. 2004 Nov;1(11):1785-99. doi: 10.1002/cbdv.200490134.
The 7-oxasphingosine (1), 7-oxaceramide (2), the thio-oxaceramide 3, and N-methyloxaceramide 4 were synthesised from D-galactose via the building block 9. The apoptosis-inducing properties of 1-4 were compared to those of sphingosine (Sph) and ceramide (Cer) using a human neuroblastoma (SK-N-BE) and a murine-promyelocyte-derived (32d) cell line. There were no differences between 2-4 and Cer in terms of their effects on the viability of cells and their ability to trigger cell proliferation. However, in the presence of N,N-dimethylsphingosine, an inhibitor of sphingosine kinase (SPHK), Cer was more potent than thio-ceramide 3 in 32d cells, while thio-ceramide 3 was more potent and efficacious in SK-N-BE cells, where it showed an IC50 value of 3 nM compared to 100 nM for Cer. In both SK-N-BE and 32d cells, 7-oxasphingosine (1) and Sph were equally toxic, even in the presence of N,N-dimethylsphingosine.
7-氧杂鞘氨醇(1)、7-氧杂神经酰胺(2)、硫代氧杂神经酰胺3和N-甲基氧杂神经酰胺4是通过构建模块9由D-半乳糖合成的。使用人神经母细胞瘤(SK-N-BE)和小鼠早幼粒细胞衍生(32d)细胞系,将1-4的诱导凋亡特性与鞘氨醇(Sph)和神经酰胺(Cer)的进行了比较。2-4与Cer在对细胞活力的影响及其触发细胞增殖的能力方面没有差异。然而,在鞘氨醇激酶(SPHK)抑制剂N,N-二甲基鞘氨醇存在的情况下,在32d细胞中,Cer比硫代神经酰胺3更有效,而硫代神经酰胺3在SK-N-BE细胞中更有效,其IC50值为3 nM,而Cer为100 nM。在SK-N-BE和32d细胞中,即使在存在N,N-二甲基鞘氨醇的情况下,7-氧杂鞘氨醇(1)和Sph的毒性也是相同的。