Heterocyclic analogues of squamocin as inhibitors of mitochondrial complex I. On the role of the terminal lactone of annonaceous acetogenins.
Heterocyclic analogues of squamocin have been semisynthesized by condensation reactions between squamocin-derived alpha-keto esters and heterodinucleophiles. The strong complex I inhibitory potency of squamocin-benzimidazole, a hybrid derivative, illustrates for the first time the functional analogy existing between the terminal butenolide of annonaceous acetogenins and heteroaromatic substructures of classic inhibitors of the enzyme. This finding supports the categorization of this atypical group of inhibitors as antagonists of the ubiquinone substrates. In addition, competition experiments of squamocin-benzimidazole versus squamocin and rolliniastatin-2 suggest that the binding of this hybrid inhibitor is responsible for a negative allosteric effect at the level of the first ubiquinone-binding site (A site) of mitochondrial complex I. This result supports the existence of a large cooperatively regulated inhibitor/ubiquinone-binding pocket located within the catalytic core of the enzyme, consisting of the association of the previously defined affinity sites A and B.
Duval
Romain A
RA
Laboratoire de Pharmacognosie (BioCIS, UMR 8076 CNRS), Faculté de Pharmacie, University Paris-Sud, rue J.B. Clément, 92296 Châtenay-Malabry Cedex, France. romarinduval@hotmail.com
Lewin
Guy
G
Peris
Eva
E
Chahboune
Nadia
N
Garofano
Aurelio
A
Dröse
Stefan
S
Cortes
Diego
D
Brandt
Ulrich
U
Hocquemiller
Reynald
R
D054378:Acetogenins; D031041:Annona / Q000201:enzymology / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004952:Esters / Q000737:chemistry; D005233:Fatty Alcohols / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D007783:Lactones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction; D012428:Ruthenium / Q000737:chemistry; D012639:Seeds / Q000378:metabolism; D013379:Substrate Specificity
D054378:Acetogenins; D004791:Enzyme Inhibitors; D004952:Esters; D005233:Fatty Alcohols; D005663:Furans; D007783:Lactones; C059660:squamocin; D012428:Ruthenium; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I