Abstract
Two glucuronide prodrugs of the histone deacetylase inhibitor CI-994 were synthesized. These compounds were found to be soluble in aqueous media and stable under physiological conditions. The carbamoyl derivatisation of CI-994 significantly decreased its toxicity towards NCI-H661 lung cancer cells. Prodrug incubation with beta-glucuronidase in the culture media led efficiently to the release of the parent drug and thereby restoring its ability to decrease cell proliferation, to inhibit HDAC and to induce E-Cadherin expression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / chemical synthesis
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Antineoplastic Combined Chemotherapy Protocols / chemistry
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Benzamides
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Cadherins / genetics
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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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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Gene Expression Regulation, Neoplastic / drug effects
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Glucuronides / chemical synthesis
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Glucuronides / chemistry
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Glucuronides / pharmacology*
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Histone Deacetylase Inhibitors*
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Humans
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Hydrolysis
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Lung Neoplasms / drug therapy*
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Molecular Structure
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Phenylenediamines / chemical synthesis
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Phenylenediamines / chemistry
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Phenylenediamines / pharmacology*
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Prodrugs / chemical synthesis
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Prodrugs / chemistry
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Prodrugs / pharmacology*
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Reverse Transcriptase Polymerase Chain Reaction
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Solubility
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Stereoisomerism
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Structure-Activity Relationship
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Time Factors
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Tumor Cells, Cultured
Substances
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Benzamides
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Cadherins
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Enzyme Inhibitors
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Glucuronides
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Histone Deacetylase Inhibitors
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Phenylenediamines
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Prodrugs
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tacedinaline