Synthesis and biological evaluation of glucuronide prodrugs of the histone deacetylase inhibitor CI-994 for application in selective cancer chemotherapy

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 17; pp. 8109 - 8116
• Main Authors: Thomas, Mickaël, Clarhaut, Jonathan, Tranoy-Opalinski, Isabelle, Gesson, Jean-Pierre, Roche, Joëlle, Papot, Sébastien
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2008; Elsevier Science; Elsevier
• Subjects: Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - chemical synthesis; Antineoplastic Combined Chemotherapy Protocols - chemistry; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Cadherins - genetics; Cancer; Cell Proliferation - drug effects; Chemotherapy; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; General aspects; Glucuronides - chemical synthesis; Glucuronides - chemistry; Glucuronides - pharmacology; HDAC inhibitors; Histone Deacetylase Inhibitors; Humans; Hydrolysis; Life Sciences; Lung Neoplasms - drug therapy; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Phenylenediamines - chemical synthesis; Phenylenediamines - chemistry; Phenylenediamines - pharmacology; Prodrugs; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Solubility; Stereoisomerism; Structure-Activity Relationship; Time Factors; Tumor Cells, Cultured; β-Glucuronidase; Chemotherapy; β-Glucuronidase; HDAC inhibitors; Prodrugs; Antineoplastic agent; Lung; Cytotoxicity; Selectivity; Organic carbamate; Glucuroconjugate; Chemical synthesis; Tumor cell; Human; Enzyme; Enzyme inhibitor; Prodrug; In vitro; Biological activity; Glycosylases; Histone deacetylase inhibitor; Cell line; Glycosidases; Hydrolases; Carboxamide; Benzamide derivatives
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.07.048

Two glucuronide prodrugs of the histone deacetylase inhibitor CI-994 were synthesized and evaluated as potential selective antitumour agents. 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 β-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.