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

Cancer cells are known to overexpress specific biomarkers and receptors needed for tumor growth; therefore, targeted chemotherapies aim at blocking cancer cell proliferation by targeting such molecules. In this regard, membrane peptide transporters (PEPTs) were proved to be upregulated in several tumors and, owing to their capability to promote the cellular uptake of potentially all physiologically occurring di- and tripeptides, they can also internalize peptide-like chemotherapeutics resembling the main structural features of small peptides (i.e. peptidomimetics). Thus, they represent an excellent target for the site-specific delivery of pharmacologically active substrates acting as “Trojan horses” [1]. Accordingly, we have been designing gold(III)-peptidedithiocarbamato derivatives which could combine both the antitumor properties and reduced side-effects of the previously reported gold(III) analogues [2] with an enhanced bioavailability and tumor selectivity due to the peptide-mediated cellular internalization provided by PEPTs. Selected derivatives showed promising cytotoxic activity toward several human tumor cell lines in vitro and no cross-resistance with the reference anticancer drug cisplatin [3]. Remarkably, their chemotherapeutic properties were confirmed in vivo by inducing up to 85% and 65% reduction of breast and prostate cancer, respectively, together with negligible (or even no) organ and acute toxicity (LD50 ca. 30 mg kg-1), thus allowing the filing of an international patent for their use in cancer chemotherapy [4] as well as providing a solid starting point for them to enter Phase I clinical trials soon.