Synthesis and mixed lineage kinase activity of pyrrolocarbazole and isoindolone analogs of (+)K-252a.

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.

Citation

Robert L Hudkins, Neil W Johnson, Thelma S Angeles, George W Gessner, John P Mallamo. Synthesis and mixed lineage kinase activity of pyrrolocarbazole and isoindolone analogs of (+)K-252a. Journal of medicinal chemistry. 2007 Feb 8;50(3):433-41

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PMID: 17266195

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