Abstract
We synthesized a series of pyrimidinedione derivatives and evaluated their activities. The results indicate that compound 6, 4-[5-fluoro-2,6-dioxo-3-(tetrahydro-furan-2-yl)-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-N-hydroxy-benzamide, exhibits potent antiproliferative activity, apoptosis induction with cleavage of caspase and PARP, and enhanced tendency to inhibit HDAC6 (IC50 = 12.4 nM) activity over HDAC1 (IC50 = 1710 nM) and HDAC2 (IC50 = 5500 nM). Compound 6 also inhibits tumor growth and is less toxic than parent 4 in vivo. These data provide compelling evidence that compound 6 is a potential antitumor compound with HDAC6 targeted inhibitory activity and may be tested for preclinical investigation for cancer treatment.
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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Apoptosis / drug effects
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Cell Line, Tumor
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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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HCT116 Cells
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Histone Deacetylase 6
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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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Mice
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Mice, Nude
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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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Pyrimidinones / chemical synthesis
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Pyrimidinones / chemistry
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Pyrimidinones / pharmacology*
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Histone Deacetylase Inhibitors
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Pyrimidinones
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HDAC6 protein, human
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Histone Deacetylase 6
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Histone Deacetylases