Design, synthesis and biological assessment of N-adamantyl, substituted adamantyl and noradamantyl phthalimidines for nitrite, TNF-α and angiogenesis inhibitory activities

• Published in: Bioorganic & medicinal chemistry 2018-05, Vol.26 (8), p.1547-1559
• Main Authors: Luo, Weiming, Tweedie, David, Beedie, Shaunna L., Vargesson, Neil, Figg, William D., Greig, Nigel H., Scerba, Michael T.
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Animals; Cell Survival - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Drug Design; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Mice; Molecular Structure; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Nitrites - antagonists & inhibitors; Nitrites - metabolism; Phthalimides - chemical synthesis; Phthalimides - chemistry; Phthalimides - pharmacology; RAW 264.7 Cells; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2018.01.032

[Display omitted] 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.