Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India.
Arch Pharm (Weinheim). 2010 Mar;343(3):167-72. doi: 10.1002/ardp.200900117.
The histone deacetylase (HDAC) enzyme plays an important role in gene transcription. Inhibitors of histone deacetylases induce cell differentiation and suppress cell proliferation in tumor cells. Hydroxamates with rigid linker have displayed better inhibition profiles than those with linear and flexible aliphatic linkers. We have designed and synthesized several potential histone deacetylase inhibitors with a piperazine moiety in the linker region to test the effect of reduced linker flexibility. Inhibitors were evaluated for their inhibitory action on human HDAC3/NCoR2 and HDAC8. N-Hydroxycarboxamide derivatives (compounds 4a-d) were found to be better than N-hydroxyacetamide derivatives (compounds 6a-d) against HDAC8. Amongst the synthesized compounds, 4a (HDAC8, IC50: 3.15 microM) with no substitution in the aryl cap was the most active and promising lead for further investigations.
组蛋白去乙酰化酶 (HDAC) 酶在基因转录中发挥重要作用。组蛋白去乙酰化酶抑制剂可诱导肿瘤细胞分化并抑制细胞增殖。具有刚性连接子的羟肟酸比具有线性和柔性脂肪族连接子的羟肟酸具有更好的抑制谱。我们设计并合成了几种具有连接子区域中哌嗪部分的潜在组蛋白去乙酰化酶抑制剂，以测试降低连接子灵活性的效果。抑制剂被评估对人 HDAC3/NCoR2 和 HDAC8 的抑制作用。发现 N-羟基羧酰胺衍生物（化合物 4a-d）比 N-羟基乙酰胺衍生物（化合物 6a-d）对 HDAC8 的抑制作用更好。在所合成的化合物中，芳基帽中没有取代基的 4a（HDAC8，IC50：3.15 μM）是最活跃和最有前途的进一步研究的先导化合物。
