Enantiospecific semisynthesis of (+)-almuheptolide-A, a novel natural heptolide inhibitor of the mammalian mitochondrial respiratory chain.
The development of novel styryl lactone derivatives as bioactive compounds and the semisynthesis of both 4,5-dialkoxylated eight-membered-ring lactones with a heptolide skeleton (almuheptolide-A (1) type) and 7-alkoxylated delta-lactones with a saturated furanopyrone skeleton (etharvensin (8) type) have been successfully achieved from the chiral unsaturated alpha-pyrone altholactone (7). This new method is a direct and one-step enantiospecific alkoxylation of altholactone (7) in concentrated acid medium, followed by formation of the eight-membered-ring zeta-lactone. The reaction mechanism operating in the synthesis of the heptolide skeleton is postulated to be a direct Michael-type addition. Concerted opening of both the alpha-pyrone and tetrahydrofuran rings and subsequent intramolecular rearrangement with the ring closure lead to almuheptolide-A (1). This compound (1) and its diacetated derivative (1a) showed potent and selective inhibitory activity toward mammalian mitochondrial respiratory chain complex I. This mechanism of action, reported here for the first time, provides a possible explanation for the cytotoxic and antitumor activities previously described for related natural compounds.
Bermejo
A
A
Departamento de Farmacología, Farmacognosia y Farmacodinamia, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain.
Tormo
J R
JR
Cabedo
N
N
Estornell
E
E
Figadère
B
B
Cortes
D
D
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D002417:Cattle; D004579:Electron Transport / Q000187:drug effects*; D042967:Electron Transport Complex I; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D013237:Stereoisomerism
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I