Neural Plasticity Group, Functional and Systems Neurobiology Department, Cajal Institute (CSIC), Avda Doctor Arce, 37, 28002, Madrid, Spain.
Eur J Med Chem. 2010 May;45(5):2034-43. doi: 10.1016/j.ejmech.2010.01.015. Epub 2010 Jan 28.
O-acetyl-ganglioside neurostatin, (Galbeta1-->3GalNAcbeta1-->4[9-O-Ac Neu5Acalpha2-->8Neu5Acalpha2-->3]Galbeta1-->4Glcbeta1-->1'-ceramide), is a natural GD1b-derived inhibitor of astroblast and astrocytoma division, whose structure and purification method limits its availability and stability. Therefore, we set-up the reaction to obtain O-acetylated and O-butyrylated neurostatin analogs by chemical synthesis, in order to improve its availability and stability. The compounds antitumoral activity was evaluated on U373MG and C6 glioblastoma cells, observing that the O-acetylation-dependent increase in the inhibitory activity was enhanced by O-butyrylation, with no further improvement with the multi-substitution, pointing to the initial conformational change and the stability change as responsible of its function. These results open the possibility for the application of the neurostatin-related compounds to in-vivo tumoral models.
O-乙酰神经节苷脂神经抑素（Galβ1-->3GalNAcβ1-->4[9-O-Ac Neu5Aca2-->8Neu5Aca2-->3]Galβ1-->4Glcβ1-->1'-神经酰胺）是一种天然 GD1b 衍生的星型胶质细胞和星形细胞瘤分裂抑制剂，其结构和纯化方法限制了其可用性和稳定性。因此，我们通过化学合成建立了获得 O-乙酰化和 O-丁酰化神经抑素类似物的反应，以提高其可用性和稳定性。评估了化合物对 U373MG 和 C6 神经胶质瘤细胞的抗肿瘤活性，观察到 O-乙酰化依赖性抑制活性的增加通过 O-丁酰化得到增强，而进一步的多取代并没有进一步改善，表明其功能与初始构象变化和稳定性变化有关。这些结果为神经抑素相关化合物在体内肿瘤模型中的应用开辟了可能性。
