Synthesis and evaluation of neuroprotective 4-O-substituted chrysotoxine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease

摘要

A series of 4- O -substituted chrysotoxine ( CTX ) derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro assays indicated that four ring substituted compounds ( 2a , 2b , 3i and 3j ) exhibited significant neuroprotective effects against Aβ _(25–35) -induced toxicity in PC12 cells. The four compounds also inhibited self- and Cu ~(2+) -induced Aβ _(1–42) aggregation and acted as biometal chelators. In particular, compound 2a was a potential lead compound for AD treatment (cell viability up to 100.78% at 50 μM in Aβ _(25–35) -treated PC12 cells, 51.88% and 58.03% inhibition at 25 μM for self- and Cu ~(2+) -induced Aβ _(1–42) aggregation, respectively). A metal chelating experiment showed that compound 2a had a moderate interaction with Cu ~(2+) and Al ~(3+) . Moreover, western blot analysis showed that compound 2a attenuated Aβ-induced tau protein hyperphosphorylation at Ser199/202 and Ser396 sites. Furthermore, compound 2a could efficiently cross the blood-brain barrier (BBB) by a parallel artificial membrane permeability assay (PAMPA). In summary, these results suggested that compound 2a was a promising multifunctional compound for AD therapy.