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Synthesis, biological evaluation and toxicity of novel tetrandrine analogues

In this work, we present the design and synthesis of novel fully synthetic analogues of the bisbenzylisoquinoline tetrandrine, a molecule with numerous pharmacological properties and the potential to treat life-threatening diseases, such as viral infections and cancer. Its toxicity to liver and lung...

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Autores principales: Schütz, Ramona, Müller, Martin, Geisslinger, Franz, Vollmar, Angelika, Bartel, Karin, Bracher, Franz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Masson SAS. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473156/
https://www.ncbi.nlm.nih.gov/pubmed/32942071
http://dx.doi.org/10.1016/j.ejmech.2020.112810
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author Schütz, Ramona
Müller, Martin
Geisslinger, Franz
Vollmar, Angelika
Bartel, Karin
Bracher, Franz
author_facet Schütz, Ramona
Müller, Martin
Geisslinger, Franz
Vollmar, Angelika
Bartel, Karin
Bracher, Franz
author_sort Schütz, Ramona
collection PubMed
description In this work, we present the design and synthesis of novel fully synthetic analogues of the bisbenzylisoquinoline tetrandrine, a molecule with numerous pharmacological properties and the potential to treat life-threatening diseases, such as viral infections and cancer. Its toxicity to liver and lungs and the underlying mechanisms, however, are controversially discussed. Along this line, novel tetrandrine analogues were synthesized and biologically evaluated for their hepatotoxicity, as well as their antiproliferative and chemoresistance reversing activity on cancer cells. Previous studies suggesting CYP-mediated toxification of tetrandrine prompted us to amend/replace the suspected metabolically instable 12-methoxy group. Of note, employing several in vitro models showed that the proposed CYP3A4-driven metabolism of tetrandrine and analogues is not the major cause of hepatotoxicity. Biological characterization revealed that some of the novel tetrandrine analogues sensitized drug-resistant leukemia cells by inhibition of the P-glycoprotein. Interestingly, direct anticancer effects improved in comparison to tetrandrine, as several compounds displayed a markedly enhanced ability to reduce proliferation of drug-resistant leukemia cells and to induce cell death of liver cancer cells. Those enhanced anticancer properties were linked to influences on activation of the kinase Akt and mitochondrial events. In sum, our study clarifies the role of CYP3A4-mediated toxicity of the bisbenzylisoquinoline alkaloid tetrandrine and provides the basis for the exploitation of novel synthetic analogues for their antitumoral potential.
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spelling pubmed-74731562020-09-08 Synthesis, biological evaluation and toxicity of novel tetrandrine analogues Schütz, Ramona Müller, Martin Geisslinger, Franz Vollmar, Angelika Bartel, Karin Bracher, Franz Eur J Med Chem Research Paper In this work, we present the design and synthesis of novel fully synthetic analogues of the bisbenzylisoquinoline tetrandrine, a molecule with numerous pharmacological properties and the potential to treat life-threatening diseases, such as viral infections and cancer. Its toxicity to liver and lungs and the underlying mechanisms, however, are controversially discussed. Along this line, novel tetrandrine analogues were synthesized and biologically evaluated for their hepatotoxicity, as well as their antiproliferative and chemoresistance reversing activity on cancer cells. Previous studies suggesting CYP-mediated toxification of tetrandrine prompted us to amend/replace the suspected metabolically instable 12-methoxy group. Of note, employing several in vitro models showed that the proposed CYP3A4-driven metabolism of tetrandrine and analogues is not the major cause of hepatotoxicity. Biological characterization revealed that some of the novel tetrandrine analogues sensitized drug-resistant leukemia cells by inhibition of the P-glycoprotein. Interestingly, direct anticancer effects improved in comparison to tetrandrine, as several compounds displayed a markedly enhanced ability to reduce proliferation of drug-resistant leukemia cells and to induce cell death of liver cancer cells. Those enhanced anticancer properties were linked to influences on activation of the kinase Akt and mitochondrial events. In sum, our study clarifies the role of CYP3A4-mediated toxicity of the bisbenzylisoquinoline alkaloid tetrandrine and provides the basis for the exploitation of novel synthetic analogues for their antitumoral potential. Elsevier Masson SAS. 2020-12-01 2020-09-04 /pmc/articles/PMC7473156/ /pubmed/32942071 http://dx.doi.org/10.1016/j.ejmech.2020.112810 Text en © 2020 Elsevier Masson SAS. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Research Paper
Schütz, Ramona
Müller, Martin
Geisslinger, Franz
Vollmar, Angelika
Bartel, Karin
Bracher, Franz
Synthesis, biological evaluation and toxicity of novel tetrandrine analogues
title Synthesis, biological evaluation and toxicity of novel tetrandrine analogues
title_full Synthesis, biological evaluation and toxicity of novel tetrandrine analogues
title_fullStr Synthesis, biological evaluation and toxicity of novel tetrandrine analogues
title_full_unstemmed Synthesis, biological evaluation and toxicity of novel tetrandrine analogues
title_short Synthesis, biological evaluation and toxicity of novel tetrandrine analogues
title_sort synthesis, biological evaluation and toxicity of novel tetrandrine analogues
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473156/
https://www.ncbi.nlm.nih.gov/pubmed/32942071
http://dx.doi.org/10.1016/j.ejmech.2020.112810
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