Toward the Selective Delivery of Chemotherapeutics into Tumor Cells by Targeting Peptide Transporters: Tailored Gold-Based Anticancer Peptidomimetics

Complexes [Au^IIIX₂(dtc-Sar-AA-O­(<i>t</i>-Bu))] (AA = Gly, X = Br (<b>1</b>)/Cl (<b>2</b>); AA = Aib, X = Br (<b>3</b>)/Cl (<b>4</b>); AA = l-Phe, X = Br (<b>5</b>)/Cl (<b>6</b>)) 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^IIIBr₂(dtc-Sar-Aib-O­(<i>t</i>-Bu))] (<b>3</b>) was solved and refined. According to in vitro cytotoxicity studies, the Aib-containing complexes <b>3</b> and <b>4</b> turned out to be the most effective toward all the human tumor cell lines evaluated (PC3, DU145, 2008, C13, and L540), reporting IC₅₀ 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