Jl. Landolt et al., DETERMINATION OF STRUCTURE-ACTIVITY-RELATIONSHIPS OF ANNONACEOUS ACETOGENINS BY INHIBITION OF OXYGEN-UPTAKE IN RAT-LIVER MITOCHONDRIA, Chemico-biological interactions, 98(1), 1995, pp. 1-13
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.