Inhibitors of Sir2: Evaluation of splitomicin analogues
Inhibitors of Sir2: Evaluation of splitomicin analogues
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DOI：
10.1021/jm030473r
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发表时间：
2004-05-06
影响因子：
7.3
通讯作者：
Bedalov, A
中科院分区：
文献类型：
--
作者：
Posakony, J;Hirao, M;Bedalov, A
制备了Splitomicin(1)和41个类似物，并在基于细胞的Sir2抑制和毒性试验以及体外Sir2抑制试验中进行了评价。内酯环或萘(7-9位)取代基会降低活性，但其他萘取代(5和6位)是可以容忍的。水解性不稳定的芳香族内酯对活性很重要。内酯水解率被用作反应活性的衡量标准；水解率与抑制活性相关。最有效的Sir2抑制剂在结构上类似于1，并且具有类似于1的水解率。
Splitomicin (1) and 41 analogues were prepared and evaluated in cell-based Sir2 inhibition and toxicity assays and an in vitro Sir2 inhibition assay. Lactone ring or naphthalene (positions 7-9) substituents decrease activity, but other naphthalene substitutions (positions 5 and 6) are well-tolerated. The hydrolytically unstable aromatic lactone is important for activity. Lactone hydrolysis rates were used as a measure of reactivity; hydrolysis rates correlate with inhibitory activity. The most potent Sir2 inhibitors were structurally similar to and had hydrolysis rates similar to 1.