101. Synthesis and Mixed Lineage Kinase Activity of Pyrrolocarbazole and Isoindolone Analogs of ()K-252a.
- Author
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Robert L. Hudkins, Neil W. Johnson, Thelma S. Angeles, George W. Gessner, and John P. Mallamo
- Subjects
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CARBAZOLE , *NITROGEN , *ATOMS , *PHYSICAL & theoretical chemistry - Abstract
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 dihydronaphthyl3,4-apyrrolo3,4-ccarbazole-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. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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