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Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP 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 (Aβ) in the brain. Whereas β-secretase supports Aβ formation along the amyloidogenic processing of the β-amyloid precursor protein (βAPP), α-...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707718/ https://www.ncbi.nlm.nih.gov/pubmed/34946739 http://dx.doi.org/10.3390/molecules26247660 |
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author | Dey, Arpita Chen, Ran Li, Feng Maitra, Subhamita Hernandez, Jean-Francois Zhou, Guo-Chun Vincent, Bruno |
author_facet | Dey, Arpita Chen, Ran Li, Feng Maitra, Subhamita Hernandez, Jean-Francois Zhou, Guo-Chun Vincent, Bruno |
author_sort | Dey, Arpita |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8707718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87077182021-12-25 Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells Dey, Arpita Chen, Ran Li, Feng Maitra, Subhamita Hernandez, Jean-Francois Zhou, Guo-Chun Vincent, Bruno Molecules Article 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. MDPI 2021-12-17 /pmc/articles/PMC8707718/ /pubmed/34946739 http://dx.doi.org/10.3390/molecules26247660 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Dey, Arpita Chen, Ran Li, Feng Maitra, Subhamita Hernandez, Jean-Francois Zhou, Guo-Chun Vincent, Bruno Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells |
title | Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells |
title_full | Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells |
title_fullStr | Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells |
title_full_unstemmed | Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells |
title_short | Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells |
title_sort | synthesis and characterization of andrographolide derivatives as regulators of βapp processing in human cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707718/ https://www.ncbi.nlm.nih.gov/pubmed/34946739 http://dx.doi.org/10.3390/molecules26247660 |
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