二茂铁修饰的Aβ抑制剂的合成与性质

Synthesis and properties of Ferrocene-modified Aβ inhibitor

抑制β-淀粉样蛋白(Aβ)的纤维化是治疗阿尔茨海默病的有效途径之一,其中NH2-Leu-Pro-Phe-Phe-Asp-OH(iAβ5)是效果较好、研究较多的寡肽类Aβ抑制剂。将二茂铁基团与iAβ5结合,得到了Fc-Leu-Pro-Phe-Phe-Asp(OMe)-OMe(Fc-iAβ5)化合物。即以二茂铁甲酸和各种氨基酸为原料,以苯并三唑-1-四甲基六氟磷酸酯(HBTU)及1-羟基苯并三唑(HOBt)为耦合剂,采用液相合成法,合成了Fc-Leu-Pro-Phe-Phe-Asp(OMe)-OMe。利用IR,NMR和MS确证了Fc-iAβ5的结构。用ThT荧光探针法检测了Fc-iAβ5对β-淀粉样蛋白Aβ1-42纤维化的抑制作用。实验结果表明,Fc-iAβ5能有效地抑制Aβ1-42纤维的形成,并且能有效地分解已形成的Aβ1-42纤维,其抑制效果优于五肽iAβ5。

The aggregation of β-amyloid peptide （Aβ） plays a key role in Alzheimer＇s disease. NH2-Leu- Pro-Phe-Phe-Asp-OH （iAβ5）, a typical oligopeptide inhibitor for β-amyloid peptide （Aβ）, was modified by ferrocenyl moiety in the investigation. Fc-Leu-Pro-Phe-Phe-Asp（OMe）-OMe （Fc-iAβ5,Fc：ferrocene） was synthesized from ferrocene monocarboxylic acid and amino acids in solution using HBTU and HOBt as coupling reagents. The ferrocenyl peptide, Fc-Leu-Pro-Phe-Phe-Asp（OMe）-OMe （Fc-iAβ5）, was characterized by IR, NMR and MS. The inhibitory properties of Fc-iAβ for the aggregation of Aβ1-42 were investigated by thioflavin T （ThT） fluorescence spectroscopy in vitro. The experimental results showed that ferrocene attached iAβ5 inhibits Aβ1-42 fibrillogenesis more strongly than iAβ5 itself. Moreover, Fc-iAβ5 is able to partially disaggregate performed fibrils.