title: Special feature of mixed phosphotriester derivatives of cytarabine.
abstract: Despite the unquestionable therapeutic interest of bis(SATE) pronucleotides, a presystemic metabolism preventing the delivery of the prodrugs in target cancer cells or tumours may constitute a limitation to the in vivo development of such derivatives. In order to overcome these drawbacks several strategies have been envisaged and we report herein the application of the S-acyl-2-thioethyl (SATE) phenyl pronucleotide approach to the well-known cytotoxic nucleoside cytosine-1-beta-D-arabinofuranoside (cytarabine, araC). We describe modifications of the SATE moieties with the introduction of polar groups on the acyl residue, in order to study how these changes affect antitumoral activity and metabolic stability. Two different synthetic pathways were explored and lead to obtain the corresponding mixed derivatives in satisfactory yields. Cytotoxicity was studied in murine leukaemia cells L1210 as well as in cells derived from solid human tumours (Messa and MCF7). Biological evaluation of these compounds in cell culture experiments with nucleoside analogue-sensitive and resistant cell lines showed that the modified compounds were active at higher concentrations than unmodified cytarabine, yet were much able to partially reverse resistance due to deficient nucleoside transport or activation. These results can be correlated with an incomplete decomposition mechanism into the corresponding 5'-mononucleotide.
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-UM 1 & 2, Université Montpellier 2, Case Courrier 1705, Place E. Bataillon, 34095 Montpellier Cedex 5, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Gouy
authors.forename: Lars P
authors.initials: LP
authors.lastname: Jordheim
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lefebvre
authors.forename: Emeline
authors.initials: E
authors.lastname: Cros
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
authors.forename: Suzanne
authors.initials: S
authors.lastname: Peyrottes
authors.forename: Christian
authors.initials: C
authors.lastname: Périgaud
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D006801:Humans; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D003561:Cytarabine