Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (Complex I)

Abstract

Natural products from the plants of the family Annonaceae, collectively called Annonaceous acetogenins, are very potent inhibitors of the NADH-ubiquinone reductase (Complex I) activity of mammalian mitochondria. The properties of five of such acetogenins are compared with those of rotenone and piericidin, classical potent inhibitors of Complex I. Rolliniastatin-1 and rolliniastatin-2 are more powerful than piericidin in terms of both their inhibitory constant and the protein-dependence of their titre in bovine submitochondrial particles. These acetogenins could be considered therefore the most potent inhibitors of mammalian Complex I. Squamocin and otivarin also have an inhibitory constant lower than that of piericidin, but display a larger protein-dependence of the titre. Squamocin and otivarin, contrary to the other acetogenins, behave qualitatively like rotenone. Rolliniastatin-2 shows unique properties as its interaction, although mutually exclusive to that of piericidin, appears to be mutually non-exclusive to that of rotenone. It is the first time that a potent inhibitor of Complex I is found not to overlap the active site of rotenone.

Synthesis and Inhibition Mechanism of Δlac-Acetogenins, a Novel Type of Inhibitor of Bovine Heart Mitochondrial Complex I

“…The residue was purified by silica gel column chromatography (hexaneEtOAc, 1:1) to give the ditosyl derivative (153 mg, 96%). To a solution of the product (153 mg, 0.192 mmol) in dry THF (15 mL) was added TBAF (1.0 M in THF, 0.4 mL, 0.4 mmol) at room temperature, and the mixture was stirred at 40°C for 2 h. The reaction mixture was quenched with saturated aqueous NH 4 Cl, washed with brine, dried, and concentrated. The crude product was purified by silica gel column chromatography (hexane-EtOAc, 3:7) to afford diepoxide 16 (37.6 mg, 87%).…”

“…To the mixture was added a solution of 20 (180 mg, 0.80 mmol) in THF (2.5 mL), and the resultant mixture was stirred for 50 min at -78 to -10°C. The reaction mixture was worked up with saturated aqueous NH 4 Cl, washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-EtOAc, 1:1) to give the diol (385 mg, 82%).…”

“…To a mixture of the diol (440 mg, 0.74 mmol) and N,N-diisopropylethylamine in CH 2 Cl 2 (7 mL) at 0°C was added chloromethyl methyl ether (480 mg, 5.92 mmol), and the mixture was stirred for 10 h at room temperature. The reaction mixture was quenched with saturated aqueous NH 4 Cl, washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography (hexanes-EtOAc, 4:1) to give 22 (490 mg, 97%).…”

“…To a solution of the MOM derivative (450 mg, 0.66 mmol) in dry THF (11 mL) at 0°C was added TBAF (1.0 M in THF, 3.93 mL, 3.93 mmol), and the resultant mixture was stirred for 1 h at room temperature. The reaction mixture was worked up with saturated aqueous NH 4 Cl, washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-EtOAc, 95:5) to give the desilylated derivative (311 mg, 99%).…”

“…After 15 min, Et 2 AlCl (1.0 M in hexane, 1.4 mL, 1.4 mmol) was added, and the mixture was stirred for 1 h. To the mixture was added a 8 mL), and the resultant mixture was stirred for 1.5 h at 0°C. The reaction mixture was worked up with saturated aqueous NH 4 Cl, washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-EtOAc, 1:1) to give 26 (41 mg, 52%).…”