Rational design of gold(III)-dithiocarbamato peptidomimetics for the targeted anticancer chemotherapy

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^IIIX₂(dtc-Sar-l-Ser(t-Bu)- O(t-Bu))] (X = Br (1a)/Cl (1b)), [Au^IIIX₂(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^IIIX₂(dtc- Sar-Aib₃-O(t-Bu))] (X = Br (4a)/Cl (4b)), and [Au^IIIX ₂(dtc-Sar-Aib₃-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 ^IIICl₂(dtc-d,l-Pro-Aib₂-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 IC₅₀ 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.