Synthesis of new derivatives of boehmeriasin A and their biological evaluation in liver cancer.

Abstract

Two series of boehmeriasin A analogs have been synthesized in short and high yielding processes providing derivatives differing either in the alkaloid's pentacyclic scaffold or its peripheral substitution pattern. These series have enabled, for the first time, comparative studies into key biological properties revealing a new lead compound with exceptionally high activity against liver cancer cell lines in the picomolar range for both well (Huh7, Hep3B and HepG2) and poorly (Mahlavu, FOCUS and SNU475) differentiated cells. The cell death was characterized as apoptosis by cytochrome-C release, PARP protein cleavage and SubG1 cell cycle arrest. Subsequent testing associated apoptosis via oxidative stress with in situ formation of reactive oxygen species (ROS) and altered phospho-protein levels. Compound 19 decreased Akt protein phosphorylation which is crucially involved in liver cancer tumorigenesis. Given its simple synthetic accessibility and intriguing biological properties this new lead compound could address unmet challenges within liver cancer therapy.

• Authors: Ece Akhan Güzelcan, Ian R Baxendale, Rengul Cetin-Atalay, Marcus Baumann
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 166 Pg. 243-255 (Mar 15 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 30716712 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Phenanthrenes
• Quinolizidines
• boehmeriasin A

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Chemistry Techniques, Synthetic
• Humans
• Liver Neoplasms (pathology)
• Phenanthrenes (chemical synthesis, chemistry, pharmacology)
• Quinolizidines (chemical synthesis, chemistry, pharmacology)