Synthesis and mixed lineage kinase activity of pyrrolocarbazole and isoindolone analogs of (+)K-252a.
J Med Chem
; 50(3): 433-41, 2007 Feb 08.
Article
em En
| MEDLINE
| ID: mdl-17266195
Structural modification of the indolecarbazole natural product (+)K-252a identified structural requirements for MLK activity and a novel series of potent fused pyrrolocarbazole MLK1/3 inhibitors. The SAR revealed that the lactam regiochemistry, the shape of the heterocycle, and aryl rings B and F are important to MLK activity. Heteroatom and alkyl replacement of the N-12 and/or N-13 indole nitrogen atoms identified the nonplanar dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-7-one (8) and corresponding 5,7-dione (7) as potent cell-permeable MLK1/3 family-selective leads with in vitro activity comparable to that of (+)K-252a and determined them to be 2- to 3-fold more potent than the aglycone natural product K-252c.
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01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirróis
/
Carbazóis
/
MAP Quinase Quinase Quinases
/
Compostos Heterocíclicos de 4 ou mais Anéis
/
Indóis
Limite:
Animals
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2007
Tipo de documento:
Article