Synthesis and Inhibitory Action of Novel Acetogenin Mimics with Bovine Heart Mitochondrial Complex I

Studies on the inhibition mechanism of acetogenins, the most potent inhibitors of complex I, are useful to elucidate the structural and functional features of the terminal electron-transfer step of this enzyme. We synthesized acetogenin mimics that possess two alkyl tails without a γ-lactone ring, named Δlac-acetogenin, and examined their inhibitory action on bovine heart mitochondrial complex I. Unexpectedly, the Δlac-acetogenin carrying two n-undecanyl groups (compound 3) elicited very potent inhibition comparable to that of bullatacin. The inhibitory potency of compound 3 markedly decreased with shortening the length of either or both alkyl tails, indicating that symmetric as well as hydrophobic properties of the inhibitor are important for the inhibition. Both acetylation and deoxygenation of either or both of two OH groups adjacent to the tetrahydrofuran (THF) rings resulted in a significant decrease in inhibitory potency. These structural dependencies of the inhibitory action of Δlac-acetogenins are in marked contrast to those of ordinary acetogenins. Double-inhibitor titration of steady-state complex I activity showed that inhibition of compound 3 and bullatacin are not additive, though the inhibition site of both inhibitors is downstream of iron−sulfur cluster N2. Our results indicate that the mode of inhibitory action of Δlac-acetogenins differs from that of ordinary acetogenins. Therefore, Δlac-acetogenins can be regarded as a novel type of inhibitor acting on the terminal electron-transfer step of complex I.