Ana S C Valdeira1,2,3, Emad Darvishi3, Girma M Woldemichael3,4, John A Beutler3, Kirk R Gustafson3, Jorge A R Salvador1,2. 1. Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy , University of Coimbra , 3000-548 Coimbra , Portugal. 2. Center for Neuroscience and Cell Biology , University of Coimbra , 3004-504 Coimbra , Portugal. 3. Molecular Targets Program, Center for Cancer Research , National Cancer Institute , Frederick , Maryland 21702 , United States. 4. Basic Science Program, Leidos Biomedical Research, Inc. , Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute , Frederick , Maryland 21702-1201 , United States.
Abstract
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 GI50 (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.
A series of novel madecassic acid (1) derivatives was synthesized, and their n class="Disease">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 GI50 (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.
Authors: Petr Dzubak; Marian Hajduch; David Vydra; Alica Hustova; Miroslav Kvasnica; David Biedermann; Lenka Markova; Milan Urban; Jan Sarek Journal: Nat Prod Rep Date: 2006-05-03 Impact factor: 13.423
Authors: Jorge A R Salvador; Ana S Leal; Ana S Valdeira; Bruno M F Gonçalves; Daniela P S Alho; Sandra A C Figueiredo; Samuel M Silvestre; Vanessa I S Mendes Journal: Eur J Med Chem Date: 2017-07-14 Impact factor: 6.514