Ferrocene tripeptide Gly-Pro-Arg conjugates: synthesis and inhibitory effects on Alzheimer's Aß(1-42) fibrillogenesis and Aß-induced cytotoxicity in vitro.

Alzheimer's disease (AD) is the most common cause of dementia, and currently there is no clinical treatment to cure it or to halt its progression. Aggregation and fibril formation of ß-amyloid peptides (Aß) are central events in the pathogenesis of AD. Many efforts have been spent on the development of effective inhibitors to prevent Aß fibrillogenesis and cause disaggregation of preformed Aß fibrils. In this study, the conjugates of ferrocene and Gly-Pro-Arg (GPR) tripeptide, Boc-Gly-Pro-Arg(NO(2))-Fca-OMe (4, GPR-Fca) and Fc-Gly-Pro-Arg-OMe (7, Fc-GPR) (Fc: ferrocene; Fca: ferrocene amino acid) were synthesized by HOBT/HBTU protocol in solution. These ferrocene GPR conjugates were employed to inhibit Aß(1-42) fibrillogenesis and to disaggregate preformed Aß fibrils. The inhibitory properties of ferrocene GPR conjugates on Aß(1-42) fibrillogenesis were evaluated by thioflavin T (ThT) fluorescence assay, and confirmed by atomic force microscopy (AFM) analysis. The interaction between the ferrocene GPR conjugates and Aß(1-42) was monitored by electrochemical means. Our results showed that both GPR and GPR-Fca can significantly inhibit the fibril formation of Aß(1-42), and cause disaggregation of the preformed fibrils. As expected, GPR-Fca shows stronger inhibitory effect on Aß(1-42) fibrillogenesis than that of its parent peptide GPR. In contrast, Fc-GPR shows no inhibitory effect on fibrillogenesis of Aß(1-42). Furthermore, GPR-Fca demonstrates significantly protection against Aß-induced cytotoxicity and exhibits high resistance to proteolysis and good lipophilicity.