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

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.本研究设计并合成了一系列以吗啉代嘌呤作为封端基团的新型组蛋白去乙酰化酶（HDAC）抑制剂。部分化合物对多种人类肿瘤细胞系表现出显著的HDAC抑制活性与抗增殖作用。其中，化合物10o被鉴定为强效I类及IIb类HDAC抑制剂，具备良好的药学特性与类药性质。蛋白质印迹法（Western blot）分析进一步证实，在体外相同浓度条件下，10o较帕比司他（LBH-589）与伏立诺他（SAHA）更能有效提升乙酰化组蛋白H3的水平。在针对HCT116、MV4-11、Ramos及MM1S异种移植模型的体内药效评价中，10o的药效优于SAHA或LBH-589，且未引发显著的体重下降与毒性反应。所有研究结果均表明，10o有望成为治疗实体瘤与血液系统恶性肿瘤的适宜候选药物。