Abstract
A library of 15 novel and heretofore uncharacterized adamantyl and noradamantyl phthalimidines was synthesized and evaluated for neuroprotective and anti-angiogenic properties. Phthalimidine treatment in LPS-challenged cells effected reductions in levels of secreted TNF-α and nitrite relative to basal amounts. The primary SAR suggests nitration of adamantyl phthalimidines has marginal effect on TNF-α activity but promotes anti-nitrite activity; thioamide congeners retain anti-nitrite activity but are less effective reducing TNF-α. Site-specific nitration and thioamidation provided phthalimidine 24, effecting an 88.5% drop in nitrite concurrent with only a 4% drop in TNF-α. Notable anti-angiogenesis activity was observed for 20, 21 and 22.
Published by Elsevier Ltd.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / chemical synthesis
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Angiogenesis Inhibitors / chemistry
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Cell Survival / drug effects
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Cells, Cultured
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Dose-Response Relationship, Drug
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Drug Design*
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / pharmacology
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Mice
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Molecular Structure
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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Nitrites / antagonists & inhibitors*
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Nitrites / metabolism
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Phthalimides / chemical synthesis
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Phthalimides / chemistry
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Phthalimides / pharmacology*
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RAW 264.7 Cells
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Angiogenesis Inhibitors
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Lipopolysaccharides
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Neuroprotective Agents
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Nitrites
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Phthalimides
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Tumor Necrosis Factor-alpha
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phthalimidine