Abstract
The structure-activity relationship (SAR) of 5-substituted pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione derivatives 5 was investigated for their potential as Chk1 inhibitors for possible chemo- and radio-potentiators in anticancer chemotherapies. In silico virtual screening helped to optimize the substituent on the phenyl ring, and led to identification of the m-carbamoyl group among the 117 analogues tested. Further optimization studies focusing on the docking model of 15 in the active site of Chk1 revealed that 32b (IC(50)=2.8nM) was a more potent inhibitor than UNC-01.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Binding Sites
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Carbazoles / chemical synthesis
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Carbazoles / chemistry*
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Carbazoles / pharmacology
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Catalytic Domain
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Cell Line, Tumor
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Checkpoint Kinase 1
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Computer Simulation
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Humans
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Phthalimides / chemical synthesis*
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Phthalimides / chemistry
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Phthalimides / pharmacology
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinases / chemistry*
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Protein Kinases / metabolism
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Pyrroles / chemistry
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Structure-Activity Relationship
Substances
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5-(3-(2-(guanidino)ethylcarbamoyl)benzylaminocarboyl)-9-hydroxy-1,3-dihydropyrrolo(3,4-c)carbazole-1,3(2H,6H)-dione
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Antineoplastic Agents
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Carbazoles
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Phthalimides
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Protein Kinase Inhibitors
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Pyrroles
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Protein Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1