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Bioorg Med Chem. 2010 Aug 15;18(16):6080-8. doi: 10.1016/j.bmc.2010.06.075. Epub 2010 Jul 1.

Dimethylaminopyridine derivatives of lupane triterpenoids are potent disruptors of mitochondrial structure and function.

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  • 1Department of Anatomy, Microbiology and Pathology, University of Minnesota School of Medicine, Duluth, USA. jholy@d.umn.edu

Abstract

Development of mitochondrially-targeted drugs is receiving increasing attention because of the central roles these organelles play in energy production, reactive oxygen generation, and regulation of cell death pathways. Previous studies have demonstrated that both natural and synthetic triterpenoids can disrupt mitochondrial structure and function. In this study, we tested the ability of a number of dimethylaminopyridine (DMAP) derivatives of lupane triterpenoids to target mitochochondria in two human melanoma cell lines and an untransformed normal fibroblast line. These compounds induced a striking fragmentation and depolarization of the mitochondrial network, along with an inhibition of cell proliferation. A range of potencies among these compounds was noted, which was correlated with the number, position, and orientation of the DMAP groups. Overall, the extent of proliferation inhibition mirrored the effectiveness of mitochondrial disruption. Thus, DMAP derivatives of lupane triterpenoids can be potent mitochondrial perturbants that appear to suppress cell growth primarily via their mitochondrial effects.

Copyright 2010 Elsevier Ltd. All rights reserved.

PMID:
20673631
[PubMed - indexed for MEDLINE]
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