Definition of crucial structural factors of acetogenins, potent inhibitorsof mitochondrial complex I

Some natural acetogenins are the most potent inhibitors of bovine heart mit ochondrial complex I. These compounds are characterized by two functional u nits (i.e. hydroxylated tetrahydrofuran (THF) and alpha,beta -unsaturated g amma -lactone ring moieties) separated by a long alkyl spacer. To elucidate which structural factors of acetogenins including their active conformatio n are crucial for the potent inhibitory effect, we synthesized a series of novel acetogenin analogues possessing bis-THF rings. The present study clea rly demonstrated that the natural gamma -lactone ring is not crucial for th e potent inhibition, although this moiety is the most common structural uni t among a large number of natural acetogenins and has been suggested to be the only reactive species that directly interacts with the enzyme (Shimada et al., Biochemistry 37 (1998) 854-866). The presence of free hydroxy group (s) in the adjacent bis-THF rings was favorable, but not essential, for the potent activity. This was probably because high polarity (or hydrophilicit y), rather than hydrogen bond-donating ability, around the bis-THF rings is required to retain the inhibitor in the active conformation. Interestingly , length of the alkyl spacer proved to be a very important structural facto r for the potent activity, the optimal length being approximately 13 carbon atoms. The present study provided further strong evidence for the previous proposal (Kuwabara et al., Eur. J. Biochem. 267 (2000) 2538-2546) that the gamma -lactone and THF ring moieties act in a cooperative manner on comple x I with the support of some specific conformation of the spacer. (C) 2000 Elsevier Science B.V. All rights reserved.