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.

在本项研究中，一系列以吗啉嘌呤为封端基团的创新组蛋白脱乙酰酶（HDAC）抑制剂被设计并合成。其中，数种化合物展现出对多种人类肿瘤细胞系显著的HDAC抑制活性及抗增殖效应。尤为值得注意的是，化合物10o被确认为一类I和IIb HDAC的有效抑制剂，具有良好的药理学特征和类似药物性质。Western blot分析进一步证实，在相同的浓度下，10o在体外比泛布司他（LBH-589）和多柔比星（SAHA）更有效地增加乙酰化组蛋白H3。在HCT116、MV4-11、Ramos和MM1S异种移植模型中的体内疗效评估中，10o显示出比SAHA或LBH-589更高的疗效，且未引起显著的体重减轻和毒性。所有结果均表明，10o可作为治疗实体瘤和血液系统癌的合适候选药物。