A chemical analog of curcumin as an improved inhibitor of amyloid Abeta oligomerization.
A chemical analog of curcumin as an improved inhibitor of amyloid Abeta oligomerization.
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DOI：
10.1371/journal.pone.0031869
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Vander Jagt DL
中科院分区：
文献类型：
--
作者：
Orlando RA;Gonzales AM;Royer RE;Deck LM;Vander Jagt DL
淀粉样斑块是阿尔茨海默病（AD）神经病理学的特征性病变。这些斑块的大小和密度与认知能力下降密切相关。为了对抗这种疾病，现有的少数疗法依赖于增加神经传递的药物;然而，这种方法的成功有限，因为它只是减缓了即将到来的下降，并且未能针对AD的根本原因。淀粉样蛋白样沉积物是由Aβ肽聚集引起的，因此，通过防止Aβ聚集来减少淀粉样蛋白负荷代表了一种有吸引力的改善AD治疗手段的方法。最近的研究表明，天然产物姜黄素能够以足够的量穿过CNS中的血脑屏障，从而减少淀粉样斑块负担。基于这种生物活性，我们假设姜黄素具有使其成为开发更有效的Aβ聚集抑制剂的优良先导化合物的分子特征。为了探索这一假设，我们筛选了姜黄素类似物的文库，并鉴定了有助于姜黄素及其类似物的抗寡聚化活性的结构特征。首先，芳环之间的间隔基中的至少一个烯酮基团对于可测量的抗A β聚集活性是必需的。其次，芳环之间的不饱和碳间隔基对于抑制活性是必不可少的，因为没有一个饱和碳间隔基显示出比天然姜黄素的任何改善幅度。第三，在芳环的Meta位和对位的甲氧基和羟基取代对于改善抑制活性的一些措施似乎是必要的。最好的铅抑制剂具有与姜黄素相反的Meta位和对位取代的甲氧基和羟基，或者甲氧基或羟基位于两个位置。用甲氧基取代姜黄素上的对羟基基团的简单取代将抑制剂功能提高了6-7倍。
Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for curcumin.
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DOI：
10.3233/jad-2010-1220
发表时间：
2010
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Markesbery WR
通讯作者：
Markesbery WR
影响因子：
2.9
作者：
LeVine, H
通讯作者：
LeVine, H
影响因子：
4.2
作者：
KLUNK, WE;DEBNATH, ML;PETTEGREW, JW
通讯作者：
PETTEGREW, JW
DOI：
10.1016/j.mrgentox.2009.02.003
发表时间：
2009-04-30
影响因子：
1.9
作者：
Mendonca, Leonardo Meneghin;dos Santos, Graciela Cristina;Greggi Antunes, Lusania Maria
通讯作者：
Greggi Antunes, Lusania Maria
影响因子：
4.2
作者：
Frautschy, SA;Hu, W;Cole, GM
通讯作者：
Cole, GM