Synthesis, biological evaluation and toxicity of novel tetrandrine analogues.

Abstract

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.

• Authors: Ramona Schütz, Martin Müller, Franz Geisslinger, Angelika Vollmar, Karin Bartel, Franz Bracher
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 207 Pg. 112810 (Dec 01 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 32942071 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Quinolines
• Cytochrome P-450 CYP3A

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology, toxicity)
• Cell Line, Tumor
• Chemistry Techniques, Synthetic
• Cytochrome P-450 CYP3A (metabolism)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Quinolines (chemical synthesis, chemistry, pharmacology, toxicity)