Alkyl-substituted polyaminohydroxamic acids: a novel class of targeted histone deacetylase inhibitors.
Alkyl-substituted polyaminohydroxamic acids: a novel class of targeted histone deacetylase inhibitors.
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烷基取代的聚氨基异羟肟酸：一类新型的靶向组蛋白脱乙酰酶抑制剂。
DOI：
10.1021/jm0505009
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发表时间：
2005
影响因子：
7.3
通讯作者：
Woster,PatrickM
中科院分区：
文献类型：
--
作者：
Varghese,Sheeba;Gupta,Deepak;Baran,Tiffany;Jiemjit,Anchalee;Gore,StevenD;CaseroJr,RobertA;Woster,PatrickM
组蛋白的可逆乙酰化是真核生物基因表达调控的关键。组蛋白去乙酰化酶抑制剂曲司他汀（TSA，1）、MS-275（2）和辛二酰苯胺异羟肟酸（SAHA，3）可抑制转化细胞和人肿瘤异种移植物的生长。然而，1− 3在各种HDAC亚型之间缺乏特异性，促使我们设计和合成聚氨基异羟肟酸（PAHA）衍生物6 −21。我们认为，多环芳烃将选择性地定向染色质和相关的组蛋白的正电荷的多胺侧链。在1 μM浓度下，化合物12、15和20对HDAC的抑制率分别为74.86%、59.99%和73.85%。尽管20的HDAC抑制作用不如1，但它比2更有效，作为组蛋白高乙酰化的引发剂更有效，并且在ML-1白血病细胞中重新表达p21 Waf 1方面比2更有效。基于这些结果，PAHAs 6 − 21代表了HDAC抑制剂的一个重要的新化学类别。
The reversible acetylation of histones is critical for regulation of eukaryotic gene expression. The histone deacetylase inhibitors trichostatin (TSA,1), MS-275 (2) and suberoylanilide hydroxamic acid (SAHA,3) arrest growth in transformed cells and in human tumor xenografts. However,1−3suffer from lack of specificity among the various HDAC isoforms, prompting us to design and synthesize polyaminohydroxamic acid (PAHA) derivatives6−21. We felt that PAHAs would be selectively directed to chromatin and associated histones by the positively charged polyamine side chain. At 1 μM, compounds12,15and20inhibited HDAC by 74.86, 59.99 and 73.85%, respectively. Although20was a less potent HDAC inhibitor than1, it was more potent than2, more effective as an initiator of histone hyperacetylation, and significantly more effective than2at re-expressing p21Waf1in ML-1 leukemia cells. On the basis of these results, PAHAs6−21represent an important new chemical class of HDAC inhibitors.