Abstract
An immobilized Staurosporine aglycone isostere where one of the indole nitrogen atoms was replaced by carbon has been sequentially functionalized to generate compounds inhibiting TrkA kinase. In the first phase, initial screening of a library of C13-hydroxymethyl-7-oxo-indenopyrrolocarbazoles resulted in several potent compounds, one of which was further optimized to generate the corresponding carbamates on solid phase. Some of the major carbamate diastereomers were found to be several-fold more potent than their alcohol parents. Synthesis, SAR analysis, kinase selectivity, and anti-tumor properties of a TrkA inhibitor (12a) are discussed.
MeSH terms
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Animals
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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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Carbazoles / chemical synthesis
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Carbazoles / chemistry
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Carbazoles / pharmacology*
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Male
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Molecular Conformation
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Neoplasms, Experimental / drug therapy
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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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Pyrroles / chemistry*
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Rats
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Rats, Sprague-Dawley
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Receptor, trkA / antagonists & inhibitors*
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Small Molecule Libraries
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Staurosporine / analogs & derivatives
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Staurosporine / chemistry*
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Stereoisomerism
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Carbazoles
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Protein Kinase Inhibitors
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Pyrroles
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Small Molecule Libraries
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Receptor, trkA
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Staurosporine