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
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Animals
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CHO Cells
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Carbazoles / chemical synthesis*
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Carbazoles / chemistry
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Carbazoles / pharmacology
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Cricetinae
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Cricetulus
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Indole Alkaloids
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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MAP Kinase Kinase Kinases / antagonists & inhibitors*
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MAP Kinase Kinase Kinases / chemistry
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Models, Molecular
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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12,13-dihydro-5H,6H,14H-naphthyl(3,4-a)pyrrolo(3,4-c)carbazole-7(7H)-one
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12,13-dihydro-6H,14H-naphthyl(3,4-a)pyrrolo(3,4-c)carbazole-5,7(5H,7H)-dione
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Carbazoles
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Heterocyclic Compounds, 4 or More Rings
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Indole Alkaloids
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Indoles
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Pyrroles
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staurosporine aglycone
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MAP Kinase Kinase Kinases