Abstract
A series of pyrrole-indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3' position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50=2.19 microM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.
Publication types
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Research Support, Non-U.S. Gov't
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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Aurora Kinase B
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Aurora Kinases
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Cell Proliferation / drug effects
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Drug Screening Assays, Antitumor
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HCT116 Cells
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HT29 Cells
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HeLa Cells
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Histones / metabolism
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Models, Molecular
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Phosphorylation
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Protein Binding
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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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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Antineoplastic Agents
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Histones
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Indoles
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Pyrroles
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AURKB protein, human
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Aurora Kinase B
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Aurora Kinases
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Protein Serine-Threonine Kinases