Gamma-lactone-Functionalized antitumoral acetogenins are the most potent inhibitors of mitochondrial complex I.
To study the relevance of the terminal alpha,beta-unsaturated gamma-methyl-gamma-lactone moiety of the antitumoral acetogenins of Annonaceae for potent mitochondrial complex I inhibition, we have prepared a series of semisynthetic acetogenins with modifications only in this part of the molecule, from the natural rolliniastatin-1 (1) and cherimolin-1 (2). Some of the hydroxylated derivatives (1b, 1d and 1e) in addition to two infrequent natural beta-hydroxy gamma-methyl gamma-lactone acetogenins, laherradurin (3) and itrabin (4), are more potent complex I inhibitors than any other known compounds.
Departamento de Farmacología, Farmacognosia y Farmacodinamia, Universidad de Valencia, Spain.
J R
JR
Tormo
E
E
Estornell
T
T
Gallardo
M C
MC
González
A
A
Cavé
S
S
Granell
D
D
Cortes
M C
MC
Zafra-Polo
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D042967:Electron Transport Complex I; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019684:Magnoliopsida / Q000737:chemistry; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology*; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013367:Submitochondrial Particles / Q000187:drug effects / Q000201:enzymology
D000970:Antineoplastic Agents; D005663:Furans; D007783:Lactones; D009097:Multienzyme Complexes; C109215:cherimolin-1; C112079:isomurisolenin; C432546:itrabin; C432547:laherradurin; C061022:bullatacin; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I