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 re cently been determined to inhibit ATP production at a similar site of action and higher levels of potency as rotenone, i.e., at NADH-ubiquin one 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 ac tive as potentially new antitumor agents. In order to determine struct ural activity relationships (SARs) among these compounds, at the subce llular level, several available acetogenins have been tested. Data obt ained, from the inhibition of oxygen consumption by rat liver mitochon dria, demonstrated that all of the twenty acetogenins tested are activ e with IC50 values in the range of 15-800 nM/mg protein. The IC50 valu e of rotenone was 17 nM/mg protein. The bis-adjacent THF ring acetogen ins and the bis-nonadjacent THF ring compounds are about ten times mor e 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 comp ounds followed by the mono-THF ring group. There was some variation be tween the groups, e.g., within the bis-adjacent and mono-THF ring grou ps, the alpha,beta-unsaturated-gamma-lactones were less active than th e keto-lactones, but this observation was reversed for one of the pair s of bis-nonadjacent THF ring acetogenins. Additional hydroxylations, to a maximum of three, seemed to increase activity within all of the g roups. Before final decisions on SARs can be made, additional comparis ons of the results of this subcellular assay (as an in vitro assay) wi th the results of in vivo assays should be made. Also, future investig ations into the exact site of action within complex I and other possib le sites of action (such as the NADH oxidase of plasma membranes) need to be conducted for a mon complete understanding of the utility and p otential of this new group of very potent compounds.