Chiral gold(III)-dithiocarbamato peptidomimetics for the anticancer chemotherapy

Peptide-based anticancer drugs are attracting much interest since they can target PEPT1 and PEPT2, membrane proteins able to transfer di- and tripeptides through the cell membrane. As these proteins seem to be overexpressed in some types of tumors, [1] we recently modified our promising gold(III)-dithiocarbamato (dtc) derivatives [2,3] with peptide ligands.[4,5] Interestingly, the complexes of the type [AuIIIX2(dtc-Sar-AA-O(t-Bu))] (X = Cl, Br; AA = Gly, Aib (α-aminoisobutyric acid)) exhibited higher anticancer activity than cisplatin, together with being not toxic towards healthy cells. Peptide ligands longer than a dipeptide did not improve the biological properties of our compounds.[5] The three amino acids employed so far (Sar, Gly and Aib) are achiral. In addition, Sar and Aib are not contained in proteins, although they are naturally occurring. Therefore, we decided to investigate the role of chirality and of the protein amino acid residues on the biological activity of our leading compounds. In this communication, we report on the synthesis and characterization of a new series of complexes: [AuIIIX2(dtc-l-Pro-Aib-O(t-Bu))], [AuIIIX2(dtc-d-Pro-Aib-O(t-Bu))], [AuIIIX2(dtc-Sar-l-Ala-O(t-Bu))] and [AuIIIX2(dtc-Sar-d- Ala-O(t-Bu))]. We also prepared [AuIIIX2(dtc-Sar-Aib-OTEG)], where the introduction of TEG (triethylenglycol) is aimed at improving the water solubility of the complex. By exploiting the Wallach rule (racemates pack better), we managed to grow single crystals of [AuIIIBr2(dtc-l,d-Pro-Aib-OtBu) and solve the X-ray crystal structure. Anticancer and toxicity tests of all newly synthesized compounds are currently in progress.