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

Güzelcan, Ece Akhan; Baxendale, Ian R.; Cetin-Atalay, Rengul; Baumann, Marcus

doi:10.1016/j.ejmech.2019.01.056

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

Güzelcan, Ece Akhan; Baxendale, Ian R.; Cetin-Atalay, Rengul; Baumann, Marcus

Authors

Ece Akhan Güzelcan

Professor Ian Baxendale i.r.baxendale@durham.ac.uk
Professor

Rengul Cetin-Atalay

Marcus Baumann

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.

Citation

Güzelcan, E. A., Baxendale, I. R., Cetin-Atalay, R., & Baumann, M. (2019). Synthesis of new derivatives of boehmeriasin A and their biological evaluation in liver cancer. European Journal of Medicinal Chemistry, 166, 243-255. https://doi.org/10.1016/j.ejmech.2019.01.056

Journal Article Type	Article
Acceptance Date	Jan 23, 2019
Online Publication Date	Jan 24, 2019
Publication Date	Mar 15, 2019
Deposit Date	Jan 26, 2019
Publicly Available Date	Jan 24, 2020
Journal	European Journal of Medicinal Chemistry
Print ISSN	0223-5234
Publisher	Elsevier
Peer Reviewed	Peer Reviewed
Volume	166
Pages	243-255
DOI	https://doi.org/10.1016/j.ejmech.2019.01.056

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© 2018 This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/