Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells

Molecules

Jean-Francois Hernandez¹  Bruno Vincent²  Arpita Dey²  Subhamita Maitra²  Guo-Chun Zhou³  Ran Chen³  Feng Li³ 

[1] Institut des Biomolécules Max Mousseron, UMR5247 CNRS/Université de Montpellier/ENSCM, Faculté de Pharmacie, CEDEX 5, 34093 Montpellier, France;Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand;School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China;

关键词: Alzheimer’s disease;    βAPP;    andrographolide;    α-secretase;    β-secretase;    neuroprotection;   

DOI  :  10.3390/molecules26247660

来源: DOAJ

【 摘 要 】

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, one of the main characteristics of which is the abnormal accumulation of amyloid peptide (Aβ) in the brain. Whereas β-secretase supports Aβ formation along the amyloidogenic processing of the β-amyloid precursor protein (βAPP), α-secretase counterbalances this pathway by both preventing Aβ production and triggering the release of the neuroprotective sAPPα metabolite. Therefore, stimulating α-secretase and/or inhibiting β-secretase can be considered a promising anti-AD therapeutic track. In this context, we tested andrographolide, a labdane diterpene derived from the plant Andrographis paniculata, as well as 24 synthesized derivatives, for their ability to induce sAPPα production in cultured SH-SY5Y human neuroblastoma cells. Following several rounds of screening, we identified three hits that were subjected to full characterization. Interestingly, andrographolide (8,17-olefinic) and its close derivative 14α-(5′,7′-dichloro-8′-quinolyloxy)-3,19-acetonylidene (compound 9) behave as moderate α-secretase activators, while 14α-(2′-methyl-5′,7′-dichloro-8′-quinolyloxy)-8,9-olefinic compounds 31 (3,19-acetonylidene) and 37 (3,19-diol), whose two structures are quite similar although distant from that of andrographolide and 9, stand as β-secretase inhibitors. Importantly, these results were confirmed in human HEK293 cells and these compounds do not trigger toxicity in either cell line. Altogether, these findings may represent an encouraging starting point for the future development of andrographolide-based compounds aimed at both activating α-secretase and inhibiting β-secretase that could prove useful in our quest for the therapeutic treatment of AD.

【 授权许可】

Unknown