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Synthesis and mixed lineage kinase activity of pyrrolocarbazole and isoindolone analogs of (+)K-252a.
Hudkins, Robert L; Johnson, Neil W; Angeles, Thelma S; Gessner, George W; Mallamo, John P.
Afiliação
  • Hudkins RL; Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA. rhudkins@ cephalon.com
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.
Assuntos
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Coleções: 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
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Coleções: 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