Fang N, Rowlands J C, Casida J E
Department of Environmental Science, Policy, and Management, University of California, Berkeley 94720-3112, USA.
Chem Res Toxicol. 1997 Aug;10(8):853-8. doi: 10.1021/tx9700432.
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.
鱼藤酮树脂用作杀虫剂/杀螨剂和鱼毒剂，其所含鱼藤酮（1）、鱼藤素（2）、鱼藤酮的6a,12a -脱氢衍生物（3）和鱼藤素的6a,12a -脱氢衍生物（4）的含量逐渐减少，还含有新发现的13 -高- 13 -氧杂- 6a,12a -脱氢类似物[称为氧代脱氢鱼藤酮（5）和氧代脱氢鱼藤素（6）]。比较了这六种鱼藤酮类化合物作为NADH：泛醌氧化还原酶活性抑制剂的效力，以及对蚊幼虫、金鱼和小鼠的生物毒性和在三种哺乳动物细胞系（Hepa 1C1C7、MCF 7和NB 41A3）中的细胞毒性。尽管鱼藤酮类化合物3 - 6对鱼藤酮树脂的整体活性贡献很小，但构效关系有两个令人惊讶的方面。首先，在为期4天的细胞毒性试验中，1的活性比2高7 - 15倍，但在其他系统中并非如此。这种细胞毒性差异不是由于氧化还原酶靶点的特异性，而是由于2比1有更广泛的细胞色素P450依赖性（胡椒基丁醚敏感）解毒作用。其次，观察到脱氢鱼藤酮转化为鱼藤酮或氧代脱氢鱼藤酮后效力增加，这表明结合两种结构变化形成顺式- 13 -高- 13 -氧杂鱼藤酮（8）可能会产生最大活性。因此，用二异丁基氢化铝将5还原为反式异构体7，然后用水性吡啶将其差向异构化为与1构型相同的顺式异构体8。令人惊讶的是，8的活性比1低得多。这可以基于B/C环系统的构象变化以及A环和D环之间二面角减小（由X射线晶体学和/或分子建模确定）来解释，其遵循效力顺序，即鱼藤酮类化合物1和2 > 氧代脱氢鱼藤酮类化合物5和6 > 反式和顺式氧杂鱼藤酮类化合物7和8 > 脱氢鱼藤酮类化合物3和4。因此，新型氧杂鱼藤酮类化合物和氧代脱氢鱼藤酮类化合物有助于确定对NADH：泛醌氧化还原酶抑制和毒性最佳的构象。
