Toward the selective delivery of chemotherapeutics into tumor cells by targeting peptide transporters: tailored gold-based anticancer peptidomimetics.
Complexes [Au(III)X(2)(dtc-Sar-AA-O(t-Bu))] (AA = Gly, X = Br (1)/Cl (2); AA = Aib, X = Br (3)/Cl (4); AA = l-Phe, X = Br (5)/Cl (6)) were designed on purpose in order to obtain gold(III)-based anticancer peptidomimetics that might specifically target two peptide transporters (namely, PEPT1 and PEPT2) upregulated in several tumor cells. All the compounds were characterized by means of FT-IR and mono- and multidimensional NMR spectroscopy, and the crystal structure of [Au(III)Br(2)(dtc-Sar-Aib-O(t-Bu))] (3) was solved and refined. According to in vitro cytotoxicity studies, the Aib-containing complexes 3 and 4 turned out to be the most effective toward all the human tumor cell lines evaluated (PC3, DU145, 2008, C13, and L540), reporting IC(50) values much lower than that of cisplatin. Remarkably, they showed no cross-resistance with cisplatin itself and were proved to inhibit tumor cell proliferation by inducing either apoptosis or late apoptosis/necrosis depending on the cell lines. Biological results are here reported and discussed in terms of the structure-activity relationship.
Department of Chemical Sciences, University of Padova, Via F. Marzolo 1, Padova 35131, Italy.
Morelle Negom
MN
Kouodom
Luca
L
Ronconi
Marta
M
Celegato
Chiara
C
Nardon
Luciano
L
Marchiò
Q Ping
QP
Dou
Donatella
D
Aldinucci
Fernando
F
Formaggio
Dolores
D
Fregona
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006046:Gold; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D000074011:Peptide Transporter 1; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D027981:Symporters / Q000378:metabolism*; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D004151:Dipeptides; D000074011:Peptide Transporter 1; D057786:Peptidomimetics; D027981:Symporters; D013859:Thiocarbamates; C093694:hydrogen-coupled oligopeptide transporter PepT2; D006046:Gold