Synthesis and evaluation of neuroprotective 4-O-substituted chrysotoxine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease. Issue 27 (26th February 2016)

• Record Type: Journal Article
• Authors: Guan, Li; Hao, Yanfeng; Chen, Lei; Wei, Meng-Lin; Jiang, Qin; Liu, Wen-Yuan; Zhang, Yan-Bo; Zhang, Jie; Feng, Feng; Qu, Wei
• Is Part Of: RSC advances. Volume 6:Issue 27(2016)
• Page Start: 22827
• Page End: 22838
• Publication Date: 2016-02-26
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c5ra21313d
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : 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). Abstract : 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 and3j ) exhibited significant neuroprotective effects against Aβ25–35 -induced toxicity in PC12 cells. The four compounds also inhibited self- and Cu 2+ -induced Aβ1–42 aggregation and acted as biometal chelators. In particular, compound2a was a potential lead compound for AD treatment (cell viability up to 100.78% at 50 µM in Aβ25–35 -treated PC12 cells, 51.88% and 58.03% inhibition at 25 µM for self- and Cu 2+ -induced Aβ1–42 aggregation, respectively). A metal chelating experiment showed that compound2a had a moderate interaction with Cu 2+ and Al 3+ . Moreover, western blot analysis showed that compound2a attenuated Aβ-induced tau protein hyperphosphorylation at Ser199/202 and Ser396 sites. Furthermore, compound2a could efficiently cross the blood-brain barrier (BBB) by a parallel artificial membrane permeability assay (PAMPA). In summary, these results suggested that compound2a was a promising multifunctional compound for AD therapy.