Synthesis and biological evaluation of the suberoylanilide hydroxamic acid (SAHA) beta-glucuronide and beta-galactoside for application in selective prodrug chemotherapy.
The beta-O-glucuronide and beta-O-galactoside of SAHA have been prepared and evaluated as prodrugs for selective cancer chemotherapy (ADEPT, PMT). These new compounds are stable under physiological conditions and do not exhibit any antiproliferative activity compared to the parent drug after a 48-h treatment of H661 cells. The glucuronide derivative did not lead to the release of the drug in the presence of either Escherichia coli or bovine liver beta-glucuronidase. On the other hand, under enzymatic cleavage of galactoside prodrug by the corresponding enzyme, a rapid release of SAHA was observed demonstrating that the beta-O-galactoside of SAHA is a promising candidate for in vivo investigations.
Thomas
Mickaël
M
UMR-CNRS 6514, Synthèse et Réactivité des Substances Naturelles, Université de Poitiers, 40, Av. du Recteur Pineau, 86022 Poitiers, France.
Rivault
Freddy
F
Tranoy-Opalinski
Isabelle
I
Roche
Joëlle
J
Gesson
Jean-Pierre
JP
Papot
Sébastien
S
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002986:Clinical Trials as Topic; D005697:Galactosides / Q000138:chemical synthesis / Q000494:pharmacology; D020719:Glucuronides / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D000077337:Vorinostat
D000970:Antineoplastic Agents; D005697:Galactosides; D020719:Glucuronides; D006877:Hydroxamic Acids; D011355:Prodrugs; D000077337:Vorinostat