title: Synthesis of pyrido[2,1-a]isoquinolin-4-ones and oxazino[2,3-a]isoquinolin-4-ones: new inhibitors of mitochondrial respiratory chain.
abstract: Benzo[a]quinolizine is an important heterocyclic framework that can be found in numerous bioactive compounds. The general scheme for the synthesis of these compounds was based on the preparation of the appropriate dihydroisoquinolines by Bischler-Napieralski cyclization with good yields, followed by the Pemberton method to form the oxazinones or pyridones derivatives via acyl-ketene imine cyclocondensation. All the synthesized compounds were assayed in vitro for their ability to inhibit mitochondrial respiratory chain. Most of the tested compounds were able to inhibit the integrated electron transfer chain, measured as NADH oxidation, which includes complexes I, III and IV, in the low micromolar range. Oxazino[2,3-a]isoquinolin-4-ones displayed greater activity than their pyrido[2,1-a]isoquinolin-4-ones analogs. Indeed, the presence of a furan ring in C₂ position of oxazino[2,3-a]isoquinolin-4-ones provided the compound (1g) with the most potent biological activity. Therefore, these compounds and especially the oxazinone derivatives are in the tendency of the new less toxic antitumor agents that target mitochondrial electron transport chain in a middle range potency.
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad de Valencia, Burjassot, 46100 Valencia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Moreno
authors.forename: Nuria
authors.initials: N
authors.lastname: Cabedo
authors.forename: Agathe
authors.initials: A
authors.lastname: Boulangé
authors.forename: Javier
authors.initials: J
authors.lastname: Párraga
authors.forename: Abraham
authors.initials: A
authors.lastname: Galán
authors.forename: Stéphane
authors.initials: S
authors.lastname: Leleu
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Sanz
authors.forename: Diego
authors.initials: D
authors.lastname: Cortes
authors.forename: Xavier
authors.initials: X
authors.lastname: Franck
mesh_terms: D000818:Animals; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D009097:Multienzyme Complexes; D010078:Oxazines; D011728:Pyridones; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases
keywords: Acyl-ketene imine cyclocondensation; Benzo[a]quinolizines; Bischler–Napieralski cyclodehydration; Cytotoxicity; Respiratory chain inhibition