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

被引：64

作者：

Chen, Yong ^{[1
,2
,3
]}

Wang, Xiaoyan ^{[1
,2
]}

Xiang, Wei ^{[1
,2
]}

He, Lin ^{[1
,2
]}

Tang, Minghai ^{[1
,2
]}

Wang, Fang ^{[1
,2
]}

Wang, Taijin ^{[1
,2
]}

Yang, Zhuang ^{[1
,2
]}

Yi, Yuyao ^{[4
,5
]}

Wang, Hairong ^{[1
,2
]}

Niu, Ting ^{[4
,5
]}

Zheng, Li ^{[1
,2
]}

Lei, Lei ^{[1
,2
]}

Li, Xiaobin ^{[1
,2
]}

Song, Hang ^{[3
]}

Chen, Lijuan ^{[1
,2
]}

机构：

[1] Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, State Key Lab Biotherapy, Chengdu 610041, Peoples R China

[2] Sichuan Univ, West China Hosp, Ctr Canc, Chengdu 610041, Peoples R China

[3] Sichuan Univ, Sch Chem Engn, Chengdu 610065, Peoples R China

[4] Sichuan Univ, West China Hosp, Dept Hematol, Chengdu 610041, Peoples R China

[5] Sichuan Univ, West China Hosp, Res Lab Hematol, Chengdu 610041, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 11期

基金：

中国国家自然科学基金;

关键词：

REFRACTORY SOLID TUMORS; MOLECULE INHIBITOR; KINASE INHIBITOR; PI3; KINASE; PHASE-I; CANCER; IDENTIFICATION; DISCOVERY; HDACS; ACETYLATION;

D O I：

10.1021/acs.jmedchem.6b00579

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：5488 / 5504

页数：17

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