title: Spacer optimization of new conjugates for a melanoma-selective delivery approach.
abstract: In the search for more selective anticancer drugs, we designed and synthesized seven conjugates varying the structure of the linker connecting the 5-iodo-2'-deoxyuridine (IUdR) to the ICF 01012 melanoma-carrier for potential intratumoural specific drug release. Chemical and in vitro metabolic stability evaluations showed that, except for the ester conjugate (1), the ketal (2b), acetal (2a), carbonate (4) and carbamate (3) conjugates were compatible with our approach. The acetal (2a) and its PEGylated derivative (2c) were of particular interest for further in vivo development owing to their respective pH-dependent stability and limited metabolic degradation in order to exploit the acidic subcellular environment of malignant melanocytes to trigger the release of therapeutics upon internalization in cells.
authors: INSERM - Université d'Auvergne UMR 990, IMTV, BP 184, F-63005 Clermont-Ferrand Cedex, France.
authors: Mathieu
authors: M
authors: André
authors: Sébastien
authors: S
authors: Tarrit
authors: Marie-Joelle
authors: MJ
authors: Couret
authors: Marie-Josèphe
authors: MJ
authors: Galmier
authors: Eric
authors: E
authors: Débiton
authors: Jean-Michel
authors: JM
authors: Chezal
authors: Emmanuelle
authors: E
authors: Mounetou
mesh_terms: D000080:Acetals / Q000138:chemical synthesis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D004355:Drug Stability; D006801:Humans; D007065:Idoxuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D008545:Melanoma / Q000188:drug therapy*; D015394:Molecular Structure; D011810:Quinoxalines / Q000737:chemistry
chemical_list: D000080:Acetals; D000970:Antineoplastic Agents; C530303:N-(2-diethylaminoethyl)-6-iodoquinoxaline-2-carboxamide; D011810:Quinoxalines; C029954:5'-deoxy-5'-iodouridine; D007065:Idoxuridine