Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Female
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Histone Deacetylase Inhibitors / chemical synthesis
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / metabolism*
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Humans
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Hydroxamic Acids / chemical synthesis
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology*
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Molecular Docking Simulation
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / pathology
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Purines / chemistry
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Purines / pharmacology*
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Purines
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Histone Deacetylases
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purine