Inhibition of electron transport of rat-liver mitochondria by synthesized antimycin A analogs.
A series of antimycin A analogs was synthesized by replacement of a dilactone-ring moiety of natural antimycin A by various alkyl, substituted phenyl, substituted diphenyl ether, or amino acid ester groups. The structure-inhibitory activity relationship was studied with rat-liver mitochondria to identify roles of the dilactone-ring moiety in the inhibitor binding to a Qi reaction center of cytochrome bc1 complex. All derivatives caused further reduction of cytochrome b reduced by succinate and the oxidant-induced reduction, showing that the derivatives inhibited electron transport by interacting with a Qi reaction center. The inhibition tended to increase as the hydrophobicity of the inhibitor increased. The mode of binding of inhibitor molecules to a Qi center, which was reflected in, for example, a sigmoidal titration curve for respiratory inhibition and a time-dependent change in inhibitory activity, varied depending on structure. These results suggested that the role of the dilactone-ring moiety of antimycin A may be not only to support hydrophobic interaction with the binding domain by increasing the hydrophobicity of the molecule, as proposed earlier, but also to regulate close fitting of the salicylic acid moiety to the binding domain.
Tokutake
N
N
Department of Agricultural Chemistry, Kyoto University, Japan.
Miyoshi
H
H
Nakazato
H
H
Iwamura
H
H
D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology*; D003573:Cytochrome b Group / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D003573:Cytochrome b Group; D000968:Antimycin A