title: Anomalous structure-activity relationships of 13-homo-13-oxarotenoids and 13-homo-13-oxadehyrorotenoids.
abstract: Cube resin, used as an insecticide/miticide and piscicide, contains in decreasing amounts rotenone (1), deguelin (2), the 6a,12a-dehydro derivatives of rotenone (3) and deguelin (4), and the newly-discovered 13-homo-13-oxa-6a,12a-dehydro analogs [referred to as oxadehydrorotenone (5) and -deguelin (6)]. These six rotenoids were compared for potency as inhibitors of NADH:ubiquinone oxidoreductase activity and for organismal toxicity to mosquito larvae, goldfish, and mice and cytotoxicity in three mammalian cell lines (Hepa 1C1C7, MCF 7, and NB 41A3). Although rotenoids 3-6 contribute very little to the overall activity of cube resin, there were two surprising aspects to the structure-activity relationships. First, 1 was 7-15-fold more active than 2 in the cytotoxicity assays of 4-day duration but not in the other systems. This difference in cytotoxicity is not due to specificity at the oxidoreductase target but instead to more extensive cytochrome P450-dependent (piperonyl butoxide-sensitive) detoxification of 2 than of 1. Second, the observed potency increase on conversion of dehydrorotenone to either rotenone or oxadehydrorotenone suggests that combining both structural changes to form cis-13-homo-13-oxarotenone (8) might result in maximal activity. Accordingly, 5 was reduced with diisobutylaluminum hydride to the trans-isomer 7 and then epimerized with aqueous pyridine to the cis-isomer 8 of the same configuration as 1. Surprisingly, 8 was much less active than 1. This is rationalized on the basis of conformational changes in the B/C ring system and decreasing dihedral angle (determined by X-ray crystallography and/or molecular modeling) between the A and D rings that follow the potency order, i.e., rotenoids 1 and 2 > oxadehydrorotenoids 5 and 6 > trans- and cis-oxarotenoids 7 and 8 > dehydrorotenoids 3 and 4. Thus, the novel oxarotenoids and oxadehydrorotenoids help define the conformation optimal for NADH:ubiquinone oxidoreductase inhibition and toxicity.
authors.affiliation: Department of Environmental Science, Policy, and Management, University of California, Berkeley 94720-3112, USA.
authors.forename: N
authors.initials: N
authors.lastname: Fang
authors.forename: J C
authors.initials: JC
authors.lastname: Rowlands
authors.forename: J E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000330:Aedes; D000818:Animals; D006054:Goldfish; D006801:Humans; D007306:Insecticides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D012402:Rotenone / Q000031:analogs & derivatives / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007306:Insecticides; D012402:Rotenone; D016660:NAD(P)H Dehydrogenase (Quinone); C107676:deguelin