Open AccessMadecassic Acid Derivatives as Potential Anticancer Agents: Synthesis and Cytotoxic Evaluation
Author(s) -
Ana S. Valdeira,
Emad Darvishi,
Girma M. Woldemichael,
John A. Beutler,
Kirk R. Gustafson,
Jorge A. R. Salvador
Publication year - 2019
Publication title -
journal of natural products
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.976
H-Index - 139
eISSN - 1520-6025
pISSN - 0163-3864
DOI - 10.1021/acs.jnatprod.8b00864
Subject(s) - cytotoxicity , cell culture , cytotoxic t cell , growth inhibition , chemistry , cell growth , cancer research , biology , colorectal cancer , melanoma , stereochemistry , biochemistry , in vitro , cancer , genetics
A series of novel madecassic acid ( 1 ) derivatives was synthesized, and their cytotoxicity was evaluated against the NCI-60 panel of cancer cell lines. Several analogues exhibited broad-spectrum cytotoxic activities over all nine tumor types represented in the panel, with more potent antiproliferative activities observed against selected cancer cell lines, including multidrug-resistant phenotypes. Among them, compound 29 showed GI 50 (50% growth inhibition) values ranging from 0.3 to 0.9 μM against 26 different tumor cell lines and selectivity for one colon (COLO 205) and two melanoma (SK-MEL-5 and UACC-257) cell lines at the TGI (total growth inhibition) level. The mode of action of 29 was predicted by CellMiner bioinformatic analysis and confirmed by biochemical and cell-based experiments to involve inhibition of the DNA replication process, particularly the initiation of replication, and disruption of mitochondrial membrane potential. The present findings suggest this novel madecassic acid derivative may have potential as an anticancer therapeutic lead for both solid and hematological tumors.