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

2008; Elsevier BV; Volume: 16; Issue: 17 Linguagem: Inglês

10.1016/j.bmc.2008.07.048

1464-3391

Mickaël Thomas, Jonathan Clarhaut, Isabelle Tranoy‐Opalinski, Jean‐Pierre Gesson, Joëlle Roche, Sébastien Papot,

Epigenetics and DNA Methylation

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.