Syntheses of tricyclic pyrones and pyridinones and protection of Abeta-peptide induced MC65 neuronal cell death.
Syntheses of tricyclic pyrones and pyridinones and protection of Abeta-peptide induced MC65 neuronal cell death.
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DOI：
10.1016/j.bmcl.2008.12.060
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发表时间：
2009-02
影响因子：
2.7
通讯作者：
Sandeep Rana;H. Hong;L. Barrigan;Lee‐way Jin;D. Hua
中科院分区：
文献类型：
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作者：
Sandeep Rana;H. Hong;L. Barrigan;Lee‐way Jin;D. Hua
SβC 基因在 MC65 细胞中条件性表达淀粉样前体蛋白的 99 个残基羧基末端片段 C99，并导致细胞死亡。因此，MC65 细胞系用于鉴定与细胞内淀粉样蛋白 β (Aβ) 寡聚物相关的毒性抑制剂。降低 Aβ 肽水平、防止 Aβ 聚集或消除现有 Aβ 聚集物的化合物可用于治疗阿尔茨海默病 (AD)。此前，我们发现三环吡喃酮 (TP) 分子化合物 1 可防止 MC65 细胞死亡并抑制 Aβ 聚集。因此，合成了在C7侧链含有杂环且在2或5位含有氮的各种TP，并评估了它们的MC65细胞保护活性。含有 N3'-腺嘌呤部分的 TP（例如化合物 1 和 11）活性最强，EC50 值分别为 0.31 和 0.35μM。尽管缺乏腺嘌呤部分，三环 N5-类似物吡喃异喹啉酮 13 和 N2-类似物吡喃吡啶酮 20 的 EC50 值分别为 2.49 和 1.25μM。有必要对三环 N2-和 N5-类似物进行进一步研究。
The SβC gene is conditionally expressed a 99-residue carboxy terminal fragment, C99, of amyloid precursor protein in MC65 cells and causes cell death. Consequently, MC65 cell line was used to identify inhibitors of toxicity related to intracellular amyloid β (Aβ) oligomers. Compounds that reduce the level of Aβ peptides, prevent Aβ aggregation, or eliminate existing Aβ aggregates may be used in the treatment of Alzheimer’s disease (AD). Previously, we found that a tricyclic pyrone (TP) molecule, compound 1, prevents MC65 cell death and inhibits Aβ aggregation. Hence various TPs containing heterocycle at C7 side chain and a nitrogen at position 2 or 5 were synthesized and their MC65 cell protective activities evaluated. TPs containing N3′-adenine moiety such as compounds 1 and 11 are most active with EC50values of 0.31 and 0.35μM, respectively. EC50values of tricyclic N5-analog, pyranoisoquinolinone 13, and N2-analog, pyranopyridinone 20, are 2.49 and 1.25μM, respectively, despite the lack of adenine moiety. Further investigation of tricyclic N2- and N5-analogs is warranted.