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

J Med Chem. 2007 Feb 8;50(3):433-41. doi: 10.1021/jm051074u.

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 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.

MeSH terms

  • Animals
  • CHO Cells
  • Carbazoles / chemical synthesis*
  • Carbazoles / chemistry
  • Carbazoles / pharmacology
  • Cricetinae
  • Cricetulus
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Indole Alkaloids
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / chemistry
  • Models, Molecular
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 12,13-dihydro-5H,6H,14H-naphthyl(3,4-a)pyrrolo(3,4-c)carbazole-7(7H)-one
  • 12,13-dihydro-6H,14H-naphthyl(3,4-a)pyrrolo(3,4-c)carbazole-5,7(5H,7H)-dione
  • Carbazoles
  • Heterocyclic Compounds, 4 or More Rings
  • Indole Alkaloids
  • Indoles
  • Pyrroles
  • staurosporine aglycone
  • MAP Kinase Kinase Kinases