Journal
JOURNAL OF NATURAL PRODUCTS
Volume 82, Issue 8, Pages 2094-2105Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jnatprod.8b00864
Keywords
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Funding
- Portuguese Foundation for Science and Technology (FCT, Fundack para a Ciencia e a Tecnologia) [SFRH/BD/75806/2011]
- Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research [1ZIABC011470, 1ZIABC011568]
- U.S. federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E]
- FEDER (European Regional Development Fund) through the COMPETE 2020 Programme (Operational Programme for Competitiveness and Internationalisation) [CENTRO-01-0247-FEDER003269]
- University of Coimbra
- FEDER - European Regional Development Fund through the COMPETE Programme (Operational Programme for Competitiveness)
- FCT [REEQ/481/QUI/2006, RECI/QEQ-QFI/0168/2012, CENTRO-07-CT62-FEDER-002012]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/75806/2011] Funding Source: FCT
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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 mu M 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.
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