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HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples
Context: Discovery of pharmacologically active natural products as starting points for drug development remains important and, for reasons of consumer safety, the identification of toxicologically relevant compounds in herbal drugs. Objective: To explain, with the aid of relevant examples from our o...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Taylor & Francis
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507960/ https://www.ncbi.nlm.nih.gov/pubmed/31057026 http://dx.doi.org/10.1080/13880209.2019.1606261 |
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author | Hamburger, Matthias |
author_facet | Hamburger, Matthias |
author_sort | Hamburger, Matthias |
collection | PubMed |
description | Context: Discovery of pharmacologically active natural products as starting points for drug development remains important and, for reasons of consumer safety, the identification of toxicologically relevant compounds in herbal drugs. Objective: To explain, with the aid of relevant examples from our own research, how these goals can be achieved. Methods: An in-house technology platform comprising pre-formatted extract libraries in 96-well format, miniaturized tracking of activity in extracts via HPLC-activity profiling, structure elucidation with microprobe NMR, and in vitro and in vivo pharmacological methods were used. Results: Piperine was identified as a new scaffold for allosteric GABA(A) receptor modulators with in vivo activity that interacts at a benzodiazepine-independent binding site. Selectivity and potency were improved by iterative optimization towards synthetic piperine analogues. Dehydroevodiamine and hortiamine from the traditional Chinese herbal drug Evodiae fructus were identified as potent hERG channel blockers in vitro. The compounds induced torsades de pointes arrhythmia in animal models. Conclusions: The allosteric binding site for piperine analogues remains to be characterized and cardiac risks of herbal drugs need to be further evaluated to ensure consumer safety. |
format | Online Article Text |
id | pubmed-6507960 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-65079602019-05-17 HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples Hamburger, Matthias Pharm Biol Review Article Context: Discovery of pharmacologically active natural products as starting points for drug development remains important and, for reasons of consumer safety, the identification of toxicologically relevant compounds in herbal drugs. Objective: To explain, with the aid of relevant examples from our own research, how these goals can be achieved. Methods: An in-house technology platform comprising pre-formatted extract libraries in 96-well format, miniaturized tracking of activity in extracts via HPLC-activity profiling, structure elucidation with microprobe NMR, and in vitro and in vivo pharmacological methods were used. Results: Piperine was identified as a new scaffold for allosteric GABA(A) receptor modulators with in vivo activity that interacts at a benzodiazepine-independent binding site. Selectivity and potency were improved by iterative optimization towards synthetic piperine analogues. Dehydroevodiamine and hortiamine from the traditional Chinese herbal drug Evodiae fructus were identified as potent hERG channel blockers in vitro. The compounds induced torsades de pointes arrhythmia in animal models. Conclusions: The allosteric binding site for piperine analogues remains to be characterized and cardiac risks of herbal drugs need to be further evaluated to ensure consumer safety. Taylor & Francis 2019-05-06 /pmc/articles/PMC6507960/ /pubmed/31057026 http://dx.doi.org/10.1080/13880209.2019.1606261 Text en © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Review Article Hamburger, Matthias HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples |
title | HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples |
title_full | HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples |
title_fullStr | HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples |
title_full_unstemmed | HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples |
title_short | HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples |
title_sort | hplc-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507960/ https://www.ncbi.nlm.nih.gov/pubmed/31057026 http://dx.doi.org/10.1080/13880209.2019.1606261 |
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