Abstract
A one-pot synthesis of ageladine A and analogues is reported. The key Pictet-Spengler reaction between 2-aminohistamine and aryl aldehydes has been successfully utilized for the synthesis of the natural product and 14 analogues. These compounds were screened for their matrix metalloprotease (MMP) and kinase inhibition to develop the first structure-activity relationship of ageladine A analogues. One compound, which showed significant kinase activity but little MMP inhibitory activity, was found to be highly active in an antiangiogenic screen, suggesting that the angiogenic activity of ageladine A is not associated with MMP inhibition but rather kinase inhibitory activity. Cytotoxicity was excluded as a mode of action by the assay of ageladine A and an analogue against 60 human cell lines.
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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Antineoplastic Agents / therapeutic use
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Humans
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Inhibitory Concentration 50
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Matrix Metalloproteinase Inhibitors
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Neovascularization, Pathologic / 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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Protein Kinase Inhibitors / therapeutic use
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Protein Kinases / metabolism
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Pyrroles / therapeutic use
Substances
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Ageladine A
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Antineoplastic Agents
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Matrix Metalloproteinase Inhibitors
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Protein Kinase Inhibitors
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Pyrroles
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Protein Kinases