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A series of novel 5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one derivatives bearing a hydroxamic acid, 2-aminoanilide and hydrazide moieties as zinc-binding group (ZBG) were designed, synthesized and evaluated for the HDAC inhibition activity and antiproliferative activity. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds IVa, IVb, IXa and IXb exhibited significant anti-proliferative activity against the three cell lines tested compared to SAHA as a reference. Compound IVb is equipotent inhibitor for HDAC1 and HDAC2 as SAHA. It is evident that the presence of free hydroxamic acid group is essential for Zn binding affinity with maximal activity with a linker of aliphatic 6 carbons. Docking study results revealed that compound IVb could occupy the HDAC2 binding site and had the potential to exhibit antitumor activity through HDAC inhibition, which merits further investigation. 相似文献
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Xiaofeng Jiang 《FEBS letters》2010,584(13):2926-2930
Phosphorylation of H2AX functions to recruit DNA repair complexes to sites of DNA damage. Here, we report that H2AX is constitutively acetylated on lysine 36 (H2AXK36Ac) by the CBP/p300 acetyltransferases. H2AXK36Ac is required for cells to survive exposure to ionizing radiation; however, H2AXK36Ac levels are not increased by DNA damage. Further, acetylation of H2AX did not affect phosphorylation of H2AX or the formation of DNA damage foci. Finally, cells with a double mutation in both the H2AX acetylation and phosphorylation sites were more radiosensitive than cells containing individual mutations. H2AXK36Ac is therefore a novel, constitutive histone modification located within the histone core region which regulates radiation sensitivity independently of H2AX phosphorylation. 相似文献
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对层生镰孢菌产甲壳素脱乙酰酶的发酵动力学进行了研究。通过Logistic方程分别构建层生镰孢菌细胞生长、甲壳素脱乙酰酶(CDA)合成及糖基质消耗的非结构动力学模型,并利用1stOpt软件对该模型进行了模拟,采用Origin8.0软件得到了非线性曲线拟合图形及各模型参数。结果表明,各模型预测值与实验数据能较好地拟合,层生镰孢菌细胞的比生长速率在第15.52h达到峰值(μm, x)0.160h-1;层生镰孢菌的底物比消耗速率在26.51h时达到峰值(μm, s)0.096h-1;层生镰孢菌的甲壳素脱乙酰酶比合成速率19.40h达到峰值(μm, p)0.548U/(mL·h)。模型拟合和实验数据具有良好的适应性,基本上反映了层生镰孢菌发酵产酶过程的动力学特征,为今后的工业化规模生产提供理论依据。 相似文献
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Chen PC Patil V Guerrant W Green P Oyelere AK 《Bioorganic & medicinal chemistry》2008,16(9):4839-4853
Histone deacetylase (HDAC) inhibition is a recent, clinically validated therapeutic strategy for cancer treatment. Small molecule HDAC inhibitors identified so far fall in to three distinct structural motifs: the zinc-binding group (ZBG), a hydrophobic linker, and a recognition cap group. Here we report the suitability of a 1,2,3-triazole ring as a surface recognition cap group-linking moiety in suberoylanilide hydroxamic acid-like (SAHA-like) HDAC inhibitors. Using “click” chemistry (Huisgen cycloaddition reaction), several triazole-linked SAHA-like hydroxamates were synthesized. Structure–activity relationship revealed that the position of the triazole moiety as well as the identity of the cap group markedly affected the in vitro HDAC inhibition and cell growth inhibitory activities of this class of compounds. 相似文献