Abstract
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.
Highlights
The search for novel anticancer agents from natural sources continues to be a productive strategy for the identification of new clinical candidates (Shah et al, 2013; Bandyopadhyay, 2014; Rayan et al, 2017)
The first Madecassic acid (MEA) derivative was prepared by treatment of MEA (1) with anhydrous potassium carbonate (K2CO3) and methyl iodide in DMF to afford the methyl ester 2 that was used as starting material for the following reactions
We synthetized a series of novel madecassic acid (MEA) derivatives and screened them for antitumor activity against the National Cancer Institute (NCI)-60 cancer cell line panel
Summary
The search for novel anticancer agents from natural sources continues to be a productive strategy for the identification of new clinical candidates (Shah et al, 2013; Bandyopadhyay, 2014; Rayan et al, 2017). Triterpenoids have emerged as a prominent group of plant-derived small molecules with multifunctional anticancer activities, as demonstrated by promising results in preclinical studies (Bishayee et al, 2011; Salvador et al, 2012, 2017; Wang et al, 2014; Figueiredo et al, 2017). Numerous reports have described the cellular and molecular mechanism(s) underlying the anticancer activity of triterpenoids. A significant increase of CD4+ and CD8+ T-lymphocyte subpopulations, as well as an increased secretion of IFN-γ and IL-4, was observed after madecassic acid administration, suggesting that this compound might play an important role in cancer immunotherapy. As compared to other triterpenoids, only a very limited number of derivatives of MEA have been reported and tested for antitumor activity
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