SkBQ - prooxidant addressed to mitochondria.
Oxidative stress and mitochondrial dysfunction are the key links in the chain of development of pathologies associated with the violation of cellular energy metabolism. Development of mitochondria-addressed compounds highly specific for chemical processes is one of the most promising ways to develop approaches to the treatment of inherited and age-related diseases with mitochondrial etiology. Correlation of structure and chemical activity of the test compounds from a class of lipophilic cations revealed the key role of substituents in the aromatic ring of 1,4-benzoquinones in the manifestation of high antioxidant properties. In this work, it is shown that a synthesized benzoquinone derivative conjugated in position 6 with membrane-penetrating cation of decyltriphenylphosphonium and with substituents at position 2, 3, and 5 (SkBQ) has much lower antioxidant and significantly higher prooxidant activity in comparison with similar derivatives of plasto- and toluquinone SkQ1 and SkQT1 in experiments on isolated mitochondria. At the same time, SkBQ, like SkQ1 and SkQT1, can be reduced by the respiratory chain in the center i of complex III and decrease the mitochondrial membrane potential. In cell cultures of human fibroblasts, it was revealed that SkBQ does not protect cells from apoptosis induced by hydrogen peroxide. Under the same conditions, SkQ1 and SkQT1 exhibit a powerful protective effect. Thus, SkBQ can be seen as a mitochondria-addressed prooxidant. The possibility of using SkBQ as an anticancer drug for the treatment of cancers such as prostate cancer whose cells are sensitive to mitochondrial reactive oxygen species is discussed.
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119992, Russia. mikhail.vyssokikh@gmail.com.
M Y
MY
Vyssokikh
B V
BV
Chernyak
L V
LV
Domnina
D S
DS
Esipov
O Y
OY
Ivanova
G A
GA
Korshunova
R A
RA
Symonyan
M V
MV
Skulachev
T V
TV
Zinevich
V P
VP
Skulachev
D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D016877:Oxidants / Q000737:chemistry / Q000494:pharmacology*; D010971:Plastoquinone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
C532038:10-(6'-plastoquinonyl)decyltriphenylphosphonium; C000591645:10-(p-benzoquinonyl)decyltriphenylphosphonium; C000591646:10-(p-toluquinonyl)decyltriphenylphosphonium; D000975:Antioxidants; D016227:Benzoquinones; D009943:Organophosphorus Compounds; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D010971:Plastoquinone