Asymmetric synthesis of 2,3-dihydro-2-arylquinazolin-4-ones: methodology and application to a potent fluorescent tubulin inhibitor with anticancer activity.
J Med Chem
; 51(15): 4620-31, 2008 Aug 14.
Article
en En
| MEDLINE
| ID: mdl-18610995
ABSTRACT
For several decades the 2,3-dihydroquinazolinone (DHQZ) heterocycle has been known to possess a variety of important biological and medicinal properties. Despite the many interesting facets of these molecules, synthetic access to nonracemic DHQZ analogues has remained elusive. Herein, we disclose a synthetic route that allows access to either enantiomer of a variety of DHQZ derivatives. We illustrate the utility of this chemistry with the asymmetric preparation and biological evaluation of a new chiral fluorescent tubulin binding agent with extremely potent antiproliferative properties against human cancer cells. A computational rationale for the increased potency of the (S)-enantiomer over the (R)-enantiomer is given, based on the crystal structure of alpha,beta-tubulin complexed with colchicine. Taking advantage of the inherent fluorescence of these molecules, confocal images of GMC-5-193 (compound 7) in the cytoplasm of human melanoma cells (MDA-MB-435) cells are presented.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Quinazolinas
/
Moduladores de Tubulina
/
Colorantes Fluorescentes
/
Hidrógeno
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2008
Tipo del documento:
Article
País de afiliación:
Estados Unidos