Determination of structure-activity relationships of Annonaceous acetogenins by inhibition of oxygen uptake in rat liver mitochondria.

A new group of natural compounds, the Annonaceous acetogenins, have recently been determined to inhibit ATP production at a similar site of action and higher levels of potency as rotenone, i.e., at NADH-ubiquinone oxido-reductase, complex I of the mitochondrial electron-transport chain. The acetogenins had earlier been determined to be pesticidal, antimalarial, antimicrobial, anti-parasitic, cytotoxic, and in vivo active as potentially new antitumor agents. In order to determine structural activity relationships (SARs) among these compounds, at the subcellular level, several available acetogenins have been tested. Data obtained, from the inhibition of oxygen consumption by rat liver mitochondria, demonstrated that all of the twenty acetogenins tested are active with IC50 values in the range of 15-800 nM/mg protein. The IC50 value of rotenone was 17 nM/mg protein. The bis-adjacent THF ring acetogenins and the bis-nonadjacent THF ring compounds are about ten times more active than the mono-THF ring acetogenins. Overall, 30-OH and 31-OH-bullatacinone were the most active and were slightly more active than rotenone. The least active were the 4-deoxy bis-adjacent THF ring compounds followed by the mono-THF ring group. There was some variation between the groups, e.g., within the bis-adjacent and mono-THF ring groups, the alpha, beta-unsaturated-gamma-lactones were less active than the keto-lactones, but this observation was reversed for one of the pairs of bis-nonadjacent THF ring acetogenins. Additional hydroxylations, to a maximum of three, seemed to increase activity within all of the groups. Before final decisions on SARs can be made, additional comparisons of the results of this subcellular assay (as an in vitro assay) with the results of in vivo assays should be made. Also, future investigations into the exact site of action within complex I and other possible sites of action (such as the NADH oxidase of plasma membranes) need to be conducted for a more. complete understanding of the utility and potential of this new group of very potent compounds.