Development of Purine-Based Hydroxamic Acid Derivatives: Potent Histone Deacetylase Inhibitors with Marked in Vitro and in Vivo Antitumor Activities
Development of Purine-Based Hydroxamic Acid Derivatives: Potent Histone Deacetylase Inhibitors with Marked in Vitro and in Vivo Antitumor Activities
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嘌呤基异羟肟酸衍生物的开发：具有显着体外和体内抗肿瘤活性的有效组蛋白脱乙酰酶抑制剂
DOI：
10.1021/acs.jmedchem.6b00579
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发表时间：
2016-06-09
影响因子：
7.3
通讯作者：
Chen, Lijuan
中科院分区：
文献类型：
--
作者：
Chen, Yong;Wang, Xiaoyan;Chen, Lijuan
本研究设计并合成了一系列新的组蛋白去乙酰化酶（HDAC）抑制剂，这些抑制剂以morpholinopurine为封盖基团。几种化合物对多种人类肿瘤细胞系显示出显著的HDAC抑制活性和抗增殖作用。其中，化合物100被鉴定为有效的I类和lib类HDAC抑制剂，具有良好的药理特征和类药物性质。Western blot分析进一步证实，100在体外比相同浓度的panobinostat （LBH-589）和vorinostat （SAHA）更有效地增加乙酰化组蛋白H3。在体内对HCT116、MV4-11、Ramos和MM1S异种移植模型的疗效评估中，100显示出比SAHA或lwh -589更高的疗效，且没有引起明显的体重减轻和毒性。所有结果表明，100可能是治疗实体癌和血液学癌的合适候选者。
In the present study, a series of novel histone deacetylase (HDAC) inhibitors using the morpholinopurine as the capping group were designed and synthesized. Several compounds demonstrated significant HDAC inhibitory activities and antiproliferative effects against diverse human tumor cell lines. Among them, compound 10o was identified as a potent class I and class lib HDAC inhibitor with good pharmaceutical profile and druglike properties. Western blot analysis further confirmed that 10o more effectively increased acetylated histone H3 than panobinostat (LBH-589) and vorinostat (SAHA) at the same concentration in vitro. In in vivo efficacy evaluations of HCT116, MV4-11, Ramos, and MM1S xenograft models, 10o showed higher efficacy than SAHA or LBH-589 without causing significant loss of body weight and toxicity. All the results indicated that 10o could be a suitable candidate for treatment of both solid and hematological cancer.