Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors.
Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors.
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DOI：
10.1016/j.bmcl.2013.11.072
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发表时间：
2014
影响因子：
2.7
通讯作者：
M. Taddei;E. Cini;L. Giannotti;G. Giannini;Gianfranco Battistuzzi;D. Vignola;L. Vesci;W. Cabri
中科院分区：
文献类型：
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作者：
M. Taddei;E. Cini;L. Giannotti;G. Giannini;Gianfranco Battistuzzi;D. Vignola;L. Vesci;W. Cabri
在辛二酰苯胺骨架的7位引入不同的内酰胺-羧酰胺，制备了一系列SAHA样分子。测试针对不同HDAC同种型的活性，并将数据与在位置7没有取代基的相应线性产物进行比较。一般来说，这种修饰提供了体外活性的有效增强。虽然内酰胺大小或CO/NH基团取向对抑制没有强烈影响，辛二酰酰胺片段的当代修饰在内酰胺系列中产生了不同的活性变体，其中化合物28（ST 8078 AA 1）显示出对所有I类HDAC同种型的2至10 nM的IC 50值，证明其是广谱泛抑制剂。对H460细胞的IC 50 = 0.5 μM也证实了这种与HDAC的强亲和力，将其列为迄今为止描述的最有效的HDAC抑制剂之一。
A series of SAHA-like molecules were prepared introducing different lactam-carboxyamides in position 7 of the suberoylanilide skeleton. The activity against different HDAC isoforms was tested and the data compared with the corresponding linear products, without substituent in position 7. In general, this modification provided an effective reinforcement of in vitro activity. While the lactam size or the CO/NH group orientation did not strongly influence the inhibition, the contemporary modification of the suberoylamide fragment gave vary active variants in the lactam series, with compound28(ST8078AA1) that showed IC50values between 2 and 10 nM against all Class I HDAC isoforms, demonstrating it to be a large spectrum pan-inhibitor. This strong affinity with HDAC was also confirmed by the value of IC50= 0.5 μM against H460 cells, ranking28as one of the most potent HDAC inhibitors described so far.