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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Chem. | doi: 10.3389/fchem.2018.00434

Synthesis and biological evaluation of new madecassic acid derivatives targeting ERK cascade signaling

 Jorge A. Salvador1, 2*,  Kirk Gustafson3*,  Ana Valdeira1, 2, Daniel Ritt4,  Deborah Morrison4* and James McMahon3
  • 1Faculdade de Farmácia, Universidade de Coimbra, Portugal
  • 2Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Portugal
  • 3Molecular Targets Program, Center for Cancer Research, National Cancer Institute at Frederick, United States
  • 4Cellular Growth Mechanisms Section, Center for Cancer Research, National Cancer Institute (NCI), Frederick, United States

In the present study, a series of novel madecassic acid derivatives was synthesized and screened against the National Cancer Institute’s 60 human cancer cell line panel. Among them, compounds 5, 12 and 17 displayed potent and highly differential antiproliferative activity against 80% of the tumor cells harboring the B-RafV600E mutation within the nanomolar range. Structure-activity analysis revealed that a 5-membered A ring containing an α,β-unsaturated aldehyde substituted at C-23 with a 2-furoyl group seems to be crucial to produce this particular growth inhibition signature. In silico analysis of the cytotoxicity pattern of these compounds identified two highly correlated clinically approved drugs with known B-RafV600E inhibitory activity. Follow-up analysis revealed inhibition of the ERK signaling pathway through the reduction of cellular Raf protein levels is a key mechanism of action of these compounds. In particular, 17 was the most potent compound in suppressing tumor growth of B-RafV600E-mutant cell lines and displayed the highest reduction of Raf protein levels among the tested compounds. Taken together, this study revealed that modifications of madecassic acid structure can provide molecules with potent anticancer activity against cell lines harboring the clinically relevant B-RafV600E mutation, with compound 17 identified as a promising lead for the development of new anticancer drugs.

Keywords: Madecassic acid, Synthesis, derivatives, NCI-60 cell line screening, B-RafV600E mutation, ERK cascade, Anticancer activity

Received: 07 May 2018; Accepted: 03 Sep 2018.

Edited by:

Laurent G. Désaubry, Université de Strasbourg, France

Reviewed by:

Alma Martelli, Università degli Studi di Pisa, Italy
Florence O. McCarthy, University College Cork, Ireland
Tadashi Honda, Stony Brook University, United States  

Copyright: © 2018 Salvador, Gustafson, Valdeira, Ritt, Morrison and McMahon. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Jorge A. Salvador, Faculdade de Farmácia, Universidade de Coimbra, Coimbra, Portugal, salvador@ci.uc.pt
PhD. Kirk Gustafson, National Cancer Institute at Frederick, Molecular Targets Program, Center for Cancer Research, Frederick, United States, gustafki@mail.nih.gov
PhD. Deborah Morrison, Center for Cancer Research, National Cancer Institute (NCI), Frederick, Cellular Growth Mechanisms Section, Frederick, United States, morrisod@mail.nih.gov