title: Rational design of gold(III)-dithiocarbamato peptidomimetics for the targeted anticancer chemotherapy.
abstract: As a further extension of our research work focusing on the development of gold(III)-dithiocarbamato dtc derivatives of oligopeptides as potential anticancer agents, complexes [Au(III)X(2)(dtc-Sar-L-Ser(t-Bu)-O(t-Bu))] (X=Br (1a)/Cl (1b)), [Au(III)X(2)(dtc-AA-Aib(2)-O(t-Bu))] (AA=Sar (sarcosine, N-methylglycine), X=Br (2a)/Cl (2b); AA=D,L-Pro, X=Br (3a)/Cl (3b)), [Au(III)X(2)(dtc-Sar-Aib(3)-O(t-Bu))] (X=Br (4a)/Cl (4b)), and [Au(III)X(2)(dtc-Sar-Aib(3)-Gly-OEt)] (X=Br (5a)/Cl (5b)) (Aib = "alpha"-aminoisobutyric acid, 2-methylalanine) were designed to obtain metal-based peptidomimetics that may specifically target two peptide transporters (namely, PEPT1 and PEPT2) upregulated in several human tumor cells. All the compounds were characterized by means of FT-IR and mono- and multidimensional NMR spectroscopy. According to in vitro cytotoxicity studies, complex [Au(III)Cl(2)(dtc-D,L-Pro-Aib(2)-O(t-Bu))] (3b) turned out to be the most effective toward the four human tumor cell lines evaluated (PC3, 2008, C13, and L540), for which the IC(50) values were lower than cisplatin. Remarkably, it showed no cross-resistance with cisplatin itself and was proved to inhibit tumor cell proliferation by inducing almost exclusively late apoptosis/necrosis. Biological results are here reported and discussed in terms of the structure-activity relationship.
authors.affiliation: Department of Chemical Sciences, University of Padova, Via F. Marzolo 1, Padova 35131, Italy.
authors.forename: Morelle Negom
authors.initials: MN
authors.lastname: Kouodom
authors.forename: Giulia
authors.initials: G
authors.lastname: Boscutti
authors.forename: Marta
authors.initials: M
authors.lastname: Celegato
authors.forename: Marco
authors.initials: M
authors.lastname: Crisma
authors.forename: Sergio
authors.initials: S
authors.lastname: Sitran
authors.forename: Donatella
authors.initials: D
authors.lastname: Aldinucci
authors.forename: Fernando
authors.initials: F
authors.lastname: Formaggio
authors.forename: Luca
authors.initials: L
authors.lastname: Ronconi
authors.forename: Dolores
authors.initials: D
authors.lastname: Fregona
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006046:Gold / Q000737:chemistry*; D006801:Humans; D050607:Organogold Compounds / Q000737:chemistry* / Q000494:pharmacology; D057786:Peptidomimetics / Q000737:chemistry*; D012521:Sarcosine / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D050607:Organogold Compounds; D057786:Peptidomimetics; D013859:Thiocarbamates; D006046:Gold; D002945:Cisplatin; D012521:Sarcosine