title: Melanoma-targeted delivery system (part 1): design, synthesis and evaluation of releasable disulfide drug by glutathione.
abstract: Here we describe the design and synthesis of a prodrug developed for pigmented melanoma therapy, consisting of a Melanin-Targeting Probe (MTP) conjugated to 5-iodo-2'-deoxyuridine (IUdR) with a reduction-sensitive pre-determined breaking point. Compared with the non-cleavable conjugate (17b), prodrug (17a) bearing a self-immolative disulfide linker achieved complete release of IUdR within 20 min in the presence of reducing agents such as DTT or glutathione. Analytical results also showed that prodrug (17a) was more sensitive than parent non-cleavable conjugate (17b) for a concentration range of glutathione similar to that found in the intracellular compartment of tumours.
authors.affiliation: INSERM - Université d'Auvergne, UMR 990, IMTV, BP 184, F-63005 Clermont-Ferrand Cedex, France; Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63005 Clermont-Ferrand Cedex, France.
authors.forename: Radhia
authors.initials: R
authors.lastname: El Aissi
authors.affiliation: INSERM - Université d'Auvergne, UMR 990, IMTV, BP 184, F-63005 Clermont-Ferrand Cedex, France; Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63005 Clermont-Ferrand Cedex, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Chezal
authors.affiliation: INSERM - Université d'Auvergne, UMR 990, IMTV, BP 184, F-63005 Clermont-Ferrand Cedex, France; Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63005 Clermont-Ferrand Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Tarrit
authors.affiliation: INSERM - Université d'Auvergne, UMR 990, IMTV, BP 184, F-63005 Clermont-Ferrand Cedex, France; Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63005 Clermont-Ferrand Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Chavignon
authors.affiliation: INSERM - Université d'Auvergne, UMR 990, IMTV, BP 184, F-63005 Clermont-Ferrand Cedex, France; Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63005 Clermont-Ferrand Cedex, France. Electronic address: emmanuel.moreau@udamail.fr.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Moreau
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D015195:Drug Design; D065546:Drug Liberation; D005978:Glutathione / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007065:Idoxuridine / Q000737:chemistry; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism*; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004220:Disulfides; D011355:Prodrugs; D005978:Glutathione; D007065:Idoxuridine
keywords: Disulfide linker; Glutathione; IUdR; Melanoma-targeted therapy; Prodrug