Anticancer Gold(III) Peptidomimetics: From Synthesis to in vitro and ex vivo Biological Evaluations

Abstract

Five new Au -peptidodithiocarbamato complexes of the type [Au Br (dtc-AA -AA -OR] (in which AA =N-methylglycine (Sar), l/d-Pro; AA =l/d-Ala, α-aminoisobutyric acid (Aib); R=OtBu, triethylene glycol methyl ether), differing with regard to the amino acid sequence and/or the chiral amino acid configuration, were designed to enhance tumor selectivity and bioavailability. The gold(III)-based moiety was functionalized to exploit the targeting properties of the peptidomimetic ligand toward two peptide transporters (namely PEPT1 and PEPT2), which are upregulated in several tumor cells. The compounds were synthesized and fully characterized, mainly by means of elemental analysis, one- and two-dimensional NMR spectroscopy, FT-IR, and UV/Vis spectrophotometry. The crystal structures of three compounds were also solved by X-ray diffraction. In vitro cytotoxicity studies using a panel of human tumor cell lines (A549 [non-small-cell lung carcinoma], MCF-7 [breast cancer], A2780 [ovarian carcinoma], H1975 [non-small-cell lung carcinoma], H460 [large-cell lung carcinoma], and A431 [human epidermoid carcinoma]) showed the dtc-Pro-Aib-OtBu derivative to be very effective, with GI values much lower than those of cisplatin. This complex was thus selected for evaluating stability under physiological conditions and possible interactions with serum albumin, as well in PARP-1 enzyme inhibition assays and preliminary ex vivo toxicity experiments on healthy rat tissues.

New selective thiolate gold(i) complexes inhibit the proliferation of different human cancer cells and induce apoptosis in primary cultures of mouse colon tumors

“…In the UV-vis spectra, a hyperchromic effect was observed in the 300 nm band (Figure 4), which is usually associated with the formation of Au-O bonds, something that could point hydrolysis processes. 36 In contrast to the results in PBS buffer, in the presence of DMEM, reactions of reduction were observed for complex 7. Most chemotherapeutic complexes benefit proteins present in bloodstream to achieve its target.…”

Emerging Molecular Receptors for the Specific-Target Delivery of Ruthenium and Gold Complexes into Cancer Cells

“…An extensive number of inorganic and organometallic gold and ruthenium complexes have been conjugated to several different biomolecules for targeted anticancer purposes. These include systems targeting the amino acid transporters [ 102 , 106 , 107 , 108 , 109 ], peptide transporters [ 110 , 111 ], glucose transporters [ 69 , 112 , 113 ], and vitamin transporters [ 77 , 114 , 115 , 116 , 117 , 118 ]. As our review mainly focuses on the emerging receptors for the target delivery of ruthenium and gold complexes into cancer cells, for which the use of biomolecules as delivering carriers is well-known and is out of our scope, we will not discuss them in further detail.…”

Au(iii)-Proline derivatives exhibiting selective antiproliferative activity against HepG2/SB3 apoptosis-resistant cancer cells

“…The screenings on some cancerous cell lines demonstrated that the resulting complexes exhibit antiproliferative activities similar to -or, in some cases, higher than -cisplatin. 21 To better investigate the effect mediated by the L-proline moiety on the cytotoxic properties of the gold-DTC compounds, in this work we synthetized and tested both Au(I) and Au(III) derivatives of the L-proline ester dithiocarbamate. We screened our novel compounds for their antiproliferative activity against the HepG2 cell line (human hepatocellular carcinoma), and the apoptosis-resistant HepG2/SB3 counterpart (human hepatocellular carcinoma overexpressing the anti-apoptotic protein SerpinB3).…”