10-Oximeguanacone, the First Nitrogenated Acetogenin Derivative Found To Be a Potent Inhibitor of Mitochondrial Complex I

Abstract

A new 10-keto bis-tetrahydrofuran acetogenin, guanacone (1), has been isolated from a cytotoxic extract of Annona aff. spraguei seeds. The 10-oximeguanacone derivative 1f is the first bioactive nitrogenated acetogenin found to be a very potent inhibitor of complex I. In addition, a SAR study of guanacone analogues is reported based on the titration of the NADH oxidase and NADH:ubiquinone oxidoreductase activities.

Synthesis and evaluation of verticipyrone analogues as mitochondrial complex I inhibitors

“…Such relative extents of inhibitory potencies have been noted previously for other complex I inhibitors. 1,14,15 The substrate concentration was higher in Q 1 -dependent NADH oxidation than in the integrated NADH oxidase assay (which contained only ~0.1–0.2 Mm Q 10 16,17 ), consistent with the interpretation that these inhibitors compete with ubiquinone for binding to complex I.…”

Historic Perspectives on Annonaceous Acetogenins from the Chemical Bench to Preclinical Trials

“…On the other hand, Gallardo et al made 10-oximeguanacone (56), the first bioactive nitrogenated acetogenin, which showed potent inhibition towards complex I by the titration of the NADH oxidase and NADH : ubiquinone oxidoreductase activities [138]. Duret et al semisynthesised amino derivatives from two natural AGEs, rolliniastatin-1 and squamocin.…”

Specific inhibitions of annonaceous acetogenins on class II 3-hydroxy-3-methylglutaryl coenzyme A reductase from Streptococcus pneumoniae

“…Squamocin C belonging to adjacent bis-THF type of ACGs, was less potent against the enzyme than the non-adjacent bis-THF type squamostatin A and squamostatin B, suggesting that the structure of non-adjacent bis-THF ring was more favorable for the inhibition than that of adjacent bis-THF ring, which is inconsistent with the inhibition of NADH oxidase of mitochondrial complex by ACGs. [32][33][34] …”