title: Preliminary studies of new proteasome inhibitors in the tumor targeting approach: synthesis and in vitro cytotoxicity.
abstract: The proteasome is a multicatalytic protease that plays a critical role in the cell. The control of proteasomes could, thus, provide a weapon for the treatment of cancer. Therefore, we have synthesized six new peptide aldehyde inhibitors of the proteasome linked to the N-(2-diethylaminoethyl)benzamide (BZA-CO) structure, in order to target the cytotoxic activity to malignant melanoma cells. Biological studies demonstrated the influence of length and composition of the amino acid chain on the cytotoxicity of our compounds. Among them, compound 19 presents the highest cytotoxicity (IC50 = 0.64 +/- 0.07 micromol): this cytotoxicity was maintained in the presence of BZA-CO but decreased 8-fold compared to the control MG132. Fluorescence activated cell sorter (FACS) and cytotoxic activity analysis demonstrated the selectivity of compound 19 for melanoma cells. Finally, western blottings of ubiquitinated proteins in IPC227F cells as well as proteasome assays confirmed that the cytotoxicity was linked to an inhibition of the proteasome activity.
authors.affiliation: UMR 484 INSERM-Université d'Auvergne-Centre Jean Perrin, Rue Montalembert, B.P. 184, 63005 Clermont-Ferrand Cedex, France. vivier@inserm484.u-clermont1.fr
authors.forename: Magali
authors.initials: M
authors.lastname: Vivier
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Jarrousse
authors.forename: Bernadette
authors.initials: B
authors.lastname: Bouchon
authors.forename: Marie-Josephe
authors.initials: MJ
authors.lastname: Galmier
authors.forename: Philippe
authors.initials: P
authors.lastname: Auzeloux
authors.forename: Jacques
authors.initials: J
authors.lastname: Sauzieres
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Madelmont
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D008546:Melanoma, Experimental / Q000378:metabolism; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D061988:Proteasome Inhibitors; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000447:Aldehydes; D000970:Antineoplastic Agents; D001549:Benzamides; C505982:N(1)-((diethylamino)ethyl)-N(4)-(4-methyl-1-(4-methyl-1-(4-methyl-1-oxopentan-2-ylamino)-1-oxopentan-2-ylamino)-1-oxopentan-2-yl)terephthalamide; D009842:Oligopeptides; D010455:Peptides; D010795:Phthalic Acids; D061988:Proteasome Inhibitors