%0 Journal Article %A Hudkins, Robert L. %A Johnson, Neil W. %A Angeles, Thelma S. %A Gessner, George W. %A Mallamo, John P. %D 2007 %T Synthesis and Mixed Lineage Kinase Activity of Pyrrolocarbazole and Isoindolone Analogs of (+)K-252a %U https://acs.figshare.com/articles/journal_contribution/Synthesis_and_Mixed_Lineage_Kinase_Activity_of_Pyrrolocarbazole_and_Isoindolone_Analogs_of_K_252a/3027310 %R 10.1021/jm051074u.s001 %2 https://acs.figshare.com/ndownloader/files/4729675 %K MLK activity %K aryl rings B %K SAR %K Mixed Lineage Kinase Activity %X 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. %I ACS Publications