Abstract
A new series of nitro or amino substituted pyrazolo[4,3-a]phenanthridines was synthesized in 6 steps from 5-bromo-6-nitroindazole. The evaluation of their inhibitory potency toward Pim kinases demonstrated that the nitro series could be considered as an interesting starting point for the development of new Pim kinase inhibitors, especially Pim-3. A preferential binding mode was suggested by molecular modeling experiments for nitro series and Pim-1/Pim-3 ATP-binding sites. Moreover, the most active compounds exhibited antiproliferative activities toward PC3 cells in the micromolar range.
Keywords:
In vitro antiproliferative activities; Kinase inhibitors; Pim kinases; Pyrazolo[4,3-a]phenanthridines.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Humans
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Models, Molecular
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Molecular Structure
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Phenanthridines / chemical synthesis
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Phenanthridines / chemistry
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Phenanthridines / 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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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-pim-1 / metabolism
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Structure-Activity Relationship
Substances
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Phenanthridines
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Protein Kinase Inhibitors
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Pyrazoles
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Proto-Oncogene Proteins c-pim-1
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proto-oncogene proteins pim