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

As a further extension of our research work focusing on the development of gold(III)- dithiocarbamato derivatives of oligopeptides as potential anticancer agents, complexes [AuIIIX2(dtc- Sar-L-Ser(t-Bu)-O(t-Bu))] (X = Br (1a)/Cl (1b)), [AuIIIX2(dtc-AA-Aib2-O(t-Bu))] (AA = Sar, X = Br (2a)/Cl (2b); AA = D,L-Pro, X = Br (3a)/Cl (3b)), [AuIIIX2(dtc-Sar-Aib3-O(t-Bu))] (X = Br (4a)/Cl (4b)), and [AuIIIX2(dtc-Sar-Aib3-Gly-OEt)] (X = Br (5a)/Cl (5b)) were designed on purpose in order to obtain metal-based peptidomimetics aimed at specifically targeting 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 [AuIIICl2(dtc-D,L-Pro-Aib2-O(t- Bu))] (3b) turned out to be the most effective toward all the human tumor cell lines evaluated (PC3, 2008, C13, and L540), reporting IC50 values lower than cisplatin. Remarkably, it showed no crossresistance 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.