One-pot regio- and stereoselective synthesis of α'-methoxy-γ-pyrones: biological evaluation as mitochondrial respiratory complex inhibitors.
The one-pot construction of functionalized α'-methoxy-γ-pyrones is detailed. Starting from α,α'-dimethoxy-γ-pyrone, molecular diversity is attained by a regio- and stereoselective desymmetrization using allyllithium followed by vinylogous aldol reaction. Mechanistic considerations including density functional theory calculations and insightful experiments have been gathered to shed light on this complex multistep process. To illustrate the versatility of this methodology, some of the molecules prepared were evaluated for their ability to inhibit NADH-oxidase and NADH-ubiquinone oxidoreductase. In the process, a potent new inihibitor of NADH-oxidase activity (IC(50) 44 nM) was identified.
Laboratoire des Fonctions Azotées et Oxygénées Complexes de l'IRCOF, CNRS UMR 6014 & FR 3038, Université de Rouen, Mont Saint-Aignan, France.
Helena
H
Rosso
Michaël
M
De Paolis
Valérie C
VC
Collin
Sriloy
S
Dey
Sidney M
SM
Hecht
Cristina
C
Prandi
Vincent
V
Richard
Jacques
J
Maddaluno
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D011753:Pyrones; C554148:alpha,alpha'-dimethoxy-gamma-pyrone; D009247:NADH, NADPH Oxidoreductases