Essential structural factors of annonaceous acetogenins as potent inhibitors of mitochondrial complex I

Abstract

The annonaceous acetogenins are the most potent of the known inhibitors of bovine heart mitochondrial complex I. These inhibitors act, at the terminal electron transfer step of the enzyme, in a similar way to the usual complex I inhibitors, such as piericidin A and rotenone; however, structural similarities are not apparent between the acetogenins and these known complex I inhibitors. A systematic set of isolated natural acetogenins was prepared and examined for their inhibitory actions with bovine heart mitochondrial complex I to identify the essential structural factors of these inhibitors for the exhibition of potent activity. Despite their very potent activity, the structural requirements of the acetogenins are not particularly rigid and remain somewhat ambiguous. The most common structural units, such as adjacent bis-tetrahydrofuran (THF) rings and hydroxyl groups in the 4- and/or 10-positions, were not essential for exhibiting potent activity. The stereochemistry surrounding the THF rings, surprisingly, seemed to be unimportant, which was corroborated by an exhaustive conformational space search analysis, indicating that the model compounds, with different stereochemical arrangements around the THF moieties, were in fairly good superimposition. Proper length and flexibility of the alkyl spacer moiety, which links the THF and the alpha, beta-unsaturated gamma-lactone ring moieties, were essential for the potent activity. This probably results from some sort of specific conformation of the spacer moiety which regulates the two ring moieties to locate into an optimal spatial position on the enzyme. It is, therefore, suggested that the structural specificity of the acetogenins, required for optimum inhibition, differs significantly from that of the common complex I inhibitors in which essential structural units are compactly arranged and conveniently defined. The structure-activity profile for complex I inhibition is discussed in comparison with those for other biological activities.

Synthesis and Inhibition Mechanism of Δlac-Acetogenins, a Novel Type of Inhibitor of Bovine Heart Mitochondrial Complex I

“…The inhibition of compound 2 was about 5-fold less potent than that of compound 1 (Table 1). At first sight, this difference seems to be not so significant, but it should be noted that inhibitory potencies of stereoisomers of common acetogenins are almost identical irrespective of the number of THF rings (9,12,13). Therefore, this result indicates that the effect of stereochemistry surrounding the bis-THF rings is more important for ∆lac-acetogenin than for common acetogenins.…”

“…In particular, the inhibitory potency of compound 7 possessing two n-butyl groups was equivalent to that of bullatacin, one of the most potent inhibitors of bovine complex I (4,6,9). Replacement of the n-butyl group of compound 7 with a bulky tert-butyl group little affected the activity (compound 7 vs 8).…”

Inhibitory Activities of Three Annonaceous Acetogenins on NADH Oxidase of Chicken Liver Mitochondria

“…The alkyl chain could result in some sort of specific conformation for optimal spatial position on the enzyme and produce potent activity. [11][12][13] Summarizing the above results and suggestions herein, it was initially thought that the inhibitory potency of ACG probably came from the features of a terminal 2,4-disubstituted-g-lactone combined with other functional ring units (in spite of THF or lactone) by a certain length of alkyl chain. The combination of the three structural factors would offer the basic specific conformation for a spacer on NADH oxidase.…”

“…But some reports indicated that the C 4 -OH was not important for the exhibition of potent effects. 11,12) Compound 1 was a new structural product which was characterized by two lactones linked by a alkyl chain. Compared with the weaker potency of compound 1, the greater potency of squamocin C and squamostatin B indicated that the THF possibly played a role in the optimal inhibition.…”

Synthesis, determination of the absolute configuration of tonkinelin, and inhibitory action with bovine heart mitochondrial complex I

“…Compounds 1a and 1b exhibited almost same inhibitory potency, indicating that the stereochemistry around the dihydroxyl moiety does not affect the inhibitory action. 12 It is noteworthy that compared to potent natural ordinary acetogenins such as bullatacin (IC 50 = 0.83 nM) 4 and cis-solamin (IC 50 = 2.6 nM), 13 1a and 1b are much weaker inhibitors of the enzyme. Further comparison with dihydroxy-cohibin-A (IC 50 = 20 nM), 14 which was synthesized by us, the inhibitory activity is quite weak.…”