Thomas Mickaël, Clarhaut Jonathan, Tranoy-Opalinski Isabelle, Gesson Jean-Pierre, Roche Joëlle, Papot Sébastien
UMR-CNRS 6514, Synthèse et Réactivité des Substances Naturelles, Université de Poitiers, 40 Av. du Recteur Pineau, 86022 Poitiers Cedex, France.
Bioorg Med Chem. 2008 Sep 1;16(17):8109-16. doi: 10.1016/j.bmc.2008.07.048. Epub 2008 Jul 23.
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.
合成了组蛋白脱乙酰酶抑制剂CI-994的两种葡萄糖醛酸酯前药。发现这些化合物可溶于水性介质，并在生理条件下稳定。CI-994的氨基甲酰基衍生化显著降低了其对NCI-H661肺癌细胞的毒性。前药与培养基中的β-葡萄糖醛酸酶孵育可有效导致母体药物释放，从而恢复其降低细胞增殖、抑制HDAC和诱导E-钙黏蛋白表达的能力。
