|
Title
|
|
|
|
Synthetic chromanol derivatives and their interaction with complex III in mitochondria from bovine, yeast, and leishmania
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| Synthetic chromanol derivatives (TMC4O, 6-hydroxy-2,2,7,8-tetramethyl-chroman-4-one; TMC2O, 6-hydroxy-4,4,7,8-tetramethyl-chroman-2-one; and Twin, 1,3,4,8,9,11-hexamethyl-6,12-methano-12H-dibenzo[d,g][1,3]dioxocin-2,10-diol) share structural elements with the potent inhibitor of the mitochondrial cytochrome (cyt) bc1 complex stigmatellin. Studies with isolated bovine cyt bc1 complex demonstrated that these compounds partially inhibit the mammalian enzyme. The aim of this work was to comparatively investigate these toxicological aspects of synthetic vitamin E derivatives in mitochondria of different species. The chromanols and atovaquone as reference compound were evaluated for their inhibition of the cyt bc1 activity in mitochondrial fractions from bovine hearts, yeast, and Leishmania. In addition, compounds were evaluated in vitro for their inhibitory activity against whole-cell Leishmania and mouse peritoneal macrophages. In these organisms, the chromanols showed a species-selective inhibition of the cyt bc1 activity different from that of atovaquone. While in atovaquone the side chain mediates species-selectivity, the marked differences for TMC2O and TMC4O in cyt bc1 inhibition suggests that direct substitution of the chromanol headgroup will control selectivity in these compounds. Low micromolar concentrations of TMC2O (IC50 = 9.5 ± 0.5 μM) inhibited the growth of Leishmania, and an esterified TMC2CO derivative inhibited the cyt bc1 activity with an IC50 of 4.9 ± 0.9 μM. These findings suggest that certain chromanols also exhibit beyond their antioxidative properties antileishmanial activities and that TMC2O derivatives could be useful toward the development of highly active antiprotozoal compounds. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Chemical research in toxicology / American Chemical Society. - Washington, D.C.
| |
|
Publication
|
|
|
|
Washington, D.C.
:
2011
| |
|
ISSN
|
|
|
|
0893-228X
| |
|
DOI
|
|
|
|
10.1021/TX200233C
| |
|
Volume/pages
|
|
|
|
24
:10
(2011)
, p. 1678-1685
| |
|
ISI
|
|
|
|
000295817800010
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|