Design syntheses and mitochondrial complex I inhibitory activity of novel acetogenin mimics.
Some natural acetogenins are the most potent inhibitors of mitochondrial complex I. These compounds are characterized by two functional units [i.e. hydroxylated tetrahydrofuran (THF) and alpha, beta-unsaturated gamma-lactone ring moieties] separated by a long alkyl spacer. To elucidate which structural factors of acetogenins, including their active conformation, are crucial for the potent inhibitory activity we synthesized a novel bis-acetogenin and its analogues possessing two gamma-lactone rings connected to bis-THF rings by flexible alkyl spacers. The inhibitory potency of the bis-acetogenin with bovine heart mitochondrial complex I was identical to that of bullatacin, one of the most potent natural acetogenins. This result indicated that one molecule of the bis-acetogenin does not work as two reactive inhibitors, suggesting that a gamma-lactone and the THF ring moieties act in a cooperative manner on the enzyme. In support of this, either of the two ring moieties synthesized individually showed no or very weak inhibitory effects. Moreover, combined use of the two ring moieties at various molar ratios exhibited no synergistic enhancement of the inhibitory potency. These observations indicate that both functional units work efficiently only when they are directly linked by a flexible alkyl spacer. Therefore, some specific conformation of the spacer must be important for optimal positioning of the two units in the enzyme. Furthermore, the alpha,beta-unsaturated gamma-lactone, the 4-OH group in the spacer region, the long alkyl tail attached to the THF unit and the stereochemistry surrounding the hydroxylated bis-THF rings were not crucial for the activity, although these are the most common structural features of natural acetogenins. The present study provided useful guiding principles not only for simplification of complicated acetogenin structure, but also for further wide structural modifications of these molecules.
Kuwabara
K
K
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Japan.
Takada
M
M
Iwata
J
J
Tatsumoto
K
K
Sakamoto
K
K
Iwamura
H
H
Miyoshi
H
H
D000818:Animals; D002417:Cattle; D015195:Drug Design; D042967:Electron Transport Complex I; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000138:chemical synthesis / Q000494:pharmacology*; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology; D018716:Molecular Mimicry; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D010100:Oxygen / Q000097:blood*
D004791:Enzyme Inhibitors; D005663:Furans; D007783:Lactones; C112079:isomurisolenin; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; D010100:Oxygen