title: Design, synthesis and in vitro drug release investigation of new potential 5-FU prodrugs.
abstract: In order to identify new efficient prodrugs of 5-fluorouracil (5-FU) and to develop an original targeting approach using 2-fluoro-2-deoxyglucose (FDG) as a potential drug carrier, eight original 5-FU derivatives were synthesized: 5-FU was attached by the N1 position of the pyrimidinic ring to the C1 position of the FDG structure either by direct coupling (2a) or via various spacers (3, 6a-c, 10b and 19). A new sensitive high-performance liquid chromatography method was developed to simultaneously quantify 5-FU and its derivatives in human plasma and other relevant media at physiological temperatures. Half-lives were determined from the degradation profiles of these conjugates. Slow degradation of compounds 2a, 3, 10b and 19 was observed in vitro at 37 °C, but no 5-FU release was noticed. By contrast, the in vitro drug release profiles of compounds 6a-c followed pseudo-first-order kinetics, and 5-FU was found in all the media. The antiproliferative activity of the eight compounds was assessed in vitro by a fluorometric assay against two human solid cancer cell lines and one healthy cell line. A correlation was found between the activities of the compounds and their ability to release 5-FU efficiently.
authors.affiliation: Clermont Université, Université d'Auvergne, Imagerie moléculaire et thérapie vectorisée, BP 10448, F-63000 Clermont-Ferrand, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Daumar
authors.forename: Caroline
authors.initials: C
authors.lastname: Decombat
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Chezal
authors.forename: Eric
authors.initials: E
authors.lastname: Debiton
authors.forename: Michel
authors.initials: M
authors.lastname: Madesclaire
authors.forename: Pascal
authors.initials: P
authors.lastname: Coudert
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Galmier
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers; D065546:Drug Liberation; D004355:Drug Stability; D019788:Fluorodeoxyglucose F18 / Q000097:blood / Q000737:chemistry*; D005472:Fluorouracil / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011355:Prodrugs; D019788:Fluorodeoxyglucose F18; D005472:Fluorouracil