title: New aldehyde and vinylsulfone proteasome inhibitors for targeted melanoma therapy.
abstract: The proteasome is a promising target in cancer therapy. However, it is ubiquitous and its inhibitors cause side effects. To target melanoma cells we synthesized new peptide aldehyde and vinylsulfone inhibitors of the proteasome conjugated to the melanin-targeting ligand (MTL) derived from radiotracer [(123)I]-N-(2-diethylaminoethyl)benzamide ([(123)I]BZA) or [(125)I]-N-(4-dipropylaminobutyl)-4-iodobenzamide ([(125)I]BZ18). Influence on the cytotoxicity of the benzamide alkyl side chain length and the composition of the amino acid sequence was assessed. Among the conjugates evaluated, compound 16 and 22 presented the highest cytotoxicity (IC(50), 0.71 and 0.64 μM respectively), which persisted in the presence of an MTL derived from N-(dialkylaminoalkylenyl)benzamide residue.
authors.affiliation: Clermont Université, Université d'Auvergne, Imagerie moléculaire et thérapie vectorisée, BP 10448, F-63000 Clermont-Ferrand, France. magali.vivier@u-clermont1.fr
authors.forename: Magali
authors.initials: M
authors.lastname: Vivier
authors.forename: Maryse
authors.initials: M
authors.lastname: Rapp
authors.forename: Marie-Josephe
authors.initials: MJ
authors.lastname: Galmier
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Jarrousse
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Miot-Noirault
authors.forename: Fernand
authors.initials: F
authors.lastname: Leal
authors.forename: Valérie
authors.initials: V
authors.lastname: Weber
authors.forename: Jacques
authors.initials: J
authors.lastname: Métin
authors.forename: Jacques
authors.initials: J
authors.lastname: Sauzière
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Chezal
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Madelmont
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008543:Melanins / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D058990:Molecular Targeted Therapy; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D061988:Proteasome Inhibitors; D013450:Sulfones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000447:Aldehydes; D000970:Antineoplastic Agents; D008024:Ligands; D008543:Melanins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D013450:Sulfones