Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK; Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Bioorg Med Chem. 2018 May 1;26(8):1547-1559. doi: 10.1016/j.bmc.2018.01.032. Epub 2018 Feb 10.
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.
合成并评价了 15 种新型且以前未表征的金刚烷和降金刚烷邻苯二甲酰亚胺库，以评估其神经保护和抗血管生成特性。与基础量相比，邻苯二甲酰亚胺处理 LPS 挑战的细胞可降低分泌的 TNF-α 和亚硝酸盐的水平。主要的 SAR 表明，金刚烷邻苯二甲酰亚胺的硝化对 TNF-α 活性的影响不大，但可促进抗亚硝酸盐活性；硫代酰胺同系物保留抗亚硝酸盐活性，但降低 TNF-α 的效果较差。定位特异性硝化和硫代酰胺化提供了邻苯二甲酰亚胺 24，可使亚硝酸盐降低 88.5%，同时 TNF-α 仅降低 4%。还观察到 20、21 和 22 具有显著的抗血管生成活性。
