Quantitative analysis of electron transport inhibition of rat-liver mitochondrial cytochrome bc1 complex by nitrophenols.
A series of nitrophenolic electron transport inhibitors (2-sec-butyl-4-nitro-6-substituted phenols and 2-sec-butyl-4-substituted-6-nitrophenols) of rat-liver mitochondrial cytochrome bc1 complex (cyt. bc1 complex) was synthesized. To obtain information on the three-dimensional structure of the ubiquinone redox site of cyt. bc1 complex, the structure-inhibitory activity relationship was examined by regression analysis using physiocochemical substituent parameters. The inhibitory activity increased as the hydrophobicity and the electron-withdrawing ability of the 4- and 6-substituents increased. These results indicated that hydrophobic interaction between the inhibitor molecule and the binding domain should be important and that an anionic form of nitrophenols may be the active form at the binding domain. Hydrogen-bond-acceptable 4-substituents such as methoxy and nitro groups, but not cyano group, were favorable to the inhibitory activity. This result, along with the fact that phenolic OH group was essential for the activity, suggested that nitrophenols occupy the ubiquinone redox site by forming two hydrogen-bond bridges as proposed for natural ubiquinone binding. Although a cyano group is hydrogen-bond-acceptable, hydrogen-bond formation between the 4-cyano group and the binding domain was not suggested. This result and molecular orbital calculation studies on electrostatic potential of the inhibitors suggested that hydrogen-bond donating residue may not be located in the region where the rod-like cyano (C identical to N) bond directs.
Miyoshi
H
H
Department of Agricultural Chemistry, Kyoto University, Japan.
Saitoh
I
I
Iwamura
H
H
D000818:Animals; D001665:Binding Sites; D004579:Electron Transport / Q000187:drug effects; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors*; D006860:Hydrogen Bonding; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D009596:Nitrophenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D014451:Ubiquinone / Q000737:chemistry
D009596:Nitrophenols; D014451:Ubiquinone; D014450:Electron Transport Complex III