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

Alzheimer's disease (AD) is a devastating neurodegenerative disorder, one of the main characteristics of which is the abnormal accumulation of amyloid peptide (A beta) in the brain. Whereas beta-secretase supports A beta formation along the amyloidogenic processing of the beta-amyloid precursor protein (beta APP), alpha-secretase counterbalances this pathway by both preventing A beta production and triggering the release of the neuroprotective sAPP alpha metabolite. Therefore, stimulating alpha-secretase and/or inhibiting beta-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 sAPP alpha 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 14 alpha-(5 & PRIME;,7 & PRIME;-dichloro-8 & PRIME;-quinolyloxy)-3,19-acetonylidene (compound 9) behave as moderate alpha-secretase activators, while 14 alpha-(2 & PRIME;-methyl-5 & PRIME;,7 & PRIME;-dichloro-8 & PRIME;-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 beta-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 alpha-secretase and inhibiting beta-secretase that could prove useful in our quest for the therapeutic treatment of AD.