期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 11, 页码 5488-5504出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00579
关键词
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资金
- National Key Programs of China during the 12th Five-Year Plan Period [2012ZX09103101-009]
- National Natural Science Foundation of China [81373283]
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.
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