Preparation and evaluation of trisubstituted pyrimidines as phosphatidylinositol 3-kinase inhibitors. 3-Hydroxyphenol analogues and bioisosteric replacements.
Bioorg Med Chem
; 19(2): 836-51, 2011 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-21216151
ABSTRACT
Two classes of trisubstituted pyrimidines related to PI-103 1 have been prepared and their inhibitory activities against phosphatidylinositol 3-kinase (PI3K) p110α were determined. From those with direct 6-aryl substitution compound 11a was the most potent inhibitor with an IC50 value of 62 nM, and showed similar activity against other class 1a PI3K isoforms tested, p110ß and p110γ. When a linking chain was introduced, as in the second exemplified class, compound 15f inhibited p110α with IC50 142 nM, and showed greater selectivity towards p110α. Compounds of both classes showed promising inhibition of cellular proliferation in IGROV-1 ovarian cancer cells. Among compounds designed to replace the 3-phenolic motif with structural isosteres, analogues incorporating a 4-indazolyl group possessed enzyme and cellular activities comparable to the parent phenols.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fenóis
/
Pirimidinas
/
Morfolinas
/
Inibidores de Proteínas Quinases
/
Inibidores de Fosfoinositídeo-3 Quinase
Limite:
Animals
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article