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Synthesis and Mixed Lineage Kinase Activity of Pyrrolocarbazole and Isoindolone Analogs of (+)K-252a
- Source :
- Journal of Medicinal Chemistry. 50:433-441
- Publication Year :
- 2007
- Publisher :
- American Chemical Society (ACS), 2007.
-
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.
- Subjects :
- Models, Molecular
Indoles
Stereochemistry
Carbazoles
Stereoisomerism
CHO Cells
Heterocyclic Compounds, 4 or More Rings
Chemical synthesis
Indole Alkaloids
Structure-Activity Relationship
chemistry.chemical_compound
Cricetulus
Polycyclic compound
Cricetinae
Drug Discovery
Animals
Structure–activity relationship
Pyrroles
Indole test
chemistry.chemical_classification
Aryl
MAP Kinase Kinase Kinases
Aglycone
chemistry
Lactam
Molecular Medicine
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 50
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....b1dc636c6f83eda62f02a594bd566a7a