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

As a further extension of our researchwork focusing on the development of gold(III)-dithiocarbamato dtc 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 (sarcosine, N-methylglycine), 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)) (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 compoundswere 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 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.