Development of Purine-Based Hydroxamic Acid Derivatives: Potent Histone Deacetylase Inhibitors with Marked in Vitro and in Vivo Antitumor Activities

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• 作者：Yong Chen ; Xiaoyan Wang ; Wei Xiang ; Lin He ; Minghai Tang ; Fang Wang ; Taijin Wang ; Zhuang Yang ; Yuyao Yi ; Hairong Wang ; Ting Niu ; Li Zheng ; Lei Lei ; Xiaobin Li ; Hang Song ; Lijuan Chen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：59
• 期：11
• 页码：5488-5504
• 全文大小：832K
• 年卷期：0
• ISSN：1520-4804

文摘

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 IIb 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.