Access to 3-spiroindolizines containing an isoindole ring through intra-molecular arylation of spiro-N-acyliminium species: a new family of potent farnesyltransferase inhibitors.
Org Biomol Chem
; 17(10): 2798-2808, 2019 03 06.
Article
en En
| MEDLINE
| ID: mdl-30793727
Based on N-acyliminium species, two efficient and rapid approaches to diversify spirocyclic systems connected by two different carbon centers to the isoindole ring have been developed. The imide reduction and the tandem oxidative cleavage of olefin/formyl-amide equilibration were at first selected as the key steps for these strategies. Ultimately the intramolecular α-amidoalkylation reaction was achieved through the arylation of α-acetoxy lactams or α-hydroxy lactams using, respectively, a Lewis acid or a Brønsted acid depending on the nature of N-acyliminium precursors. The latter led, in addition to the spiro-6-membered aza-heterocycles, to the formation of scarce spiro-5-membered analogues which show promising inhibitory activities on human farnesyltransferase in the nanomolar range demonstrating improved IC50 values of up to 1.5 nM.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Compuestos de Espiro
/
Inhibidores Enzimáticos
/
Farnesiltransferasa
/
Isoindoles
Idioma:
En
Revista:
Org Biomol Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Reino Unido