Synthesis and biological evaluation of glucuronide prodrugs of the histone deacetylase inhibitor CI-994 for application in selective cancer chemotherapy.
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.
Thomas
Mickaël
M
UMR-CNRS 6514, Synthèse et Réactivité des Substances Naturelles, Université de Poitiers, 40 Av. du Recteur Pineau, 86022 Poitiers Cedex, France.
Clarhaut
Jonathan
J
Tranoy-Opalinski
Isabelle
I
Gesson
Jean-Pierre
JP
Roche
Joëlle
J
Papot
Sébastien
S
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides; D015820:Cadherins / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020719:Glucuronides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006868:Hydrolysis; D008175:Lung Neoplasms / Q000188:drug therapy*; D015394:Molecular Structure; D010655:Phenylenediamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014407:Tumor Cells, Cultured
D001549:Benzamides; D015820:Cadherins; D004791:Enzyme Inhibitors; D020719:Glucuronides; D056572:Histone Deacetylase Inhibitors; D010655:Phenylenediamines; D011355:Prodrugs; C081895:tacedinaline