Synthesis and Mixed Lineage Kinase Activity of Pyrrolocarbazole and Isoindolone Analogs of (+)K-252a

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• 作者：Robert L. Hudkins ; Neil W. Johnson ; Thelma S. Angeles ; George W. Gessner ; John P. Mallamo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：February 8, 2007
• 年：2007
• 卷：50
• 期：3
• 页码：433 - 441
• 全文大小：156K
• 年卷期：v.50,no.3(February 8, 2007)
• ISSN：1520-4804

文摘

Structural modification of the indolecarbazole natural product (+)K-252a identified structural requirementsfor MLK activity and a novel series of potent fused pyrrolocarbazole MLK1/3 inhibitors. The SAR revealedthat the lactam regiochemistry, the shape of the heterocycle, and aryl rings B and F are important to MLKactivity. Heteroatom and alkyl replacement of the N-12 and/or N-13 indole nitrogen atoms identified thenonplanar dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-7-one (8) and corresponding 5,7-dione (7) as potentcell-permeable MLK1/3 family-selective leads with in vitro activity comparable to that of (+)K-252a anddetermined them to be 2- to 3-fold more potent than the aglycone natural product K-252c.