ABSTRACT
This paper deals with the combination of a proline-based moiety with biologically active gold centers in the oxidation states +1 and +3. In particular, six Au(i)/(iii)-proline dithiocarbamato (DTC) complexes with general formulae [Au(DTC)2] and [AuIIIX2(DTC)] (X = Cl, Br) are reported here. After the synthesis of the ligand and the complexes, all derivatives were characterized via several techniques and tested for their stability in DMSO/water media. This study was focused on the demonstration of a peculiar behavior of Au(iii)-DTC species in solution. Finally, the complexes were screened for their antiproliferative activity against 2 human cancer cell lines, namely HepG2 and HepG2/SB3, taken as models of hepatocellular carcinoma. The latter, chosen for its aggressiveness due to the upregulation of the anti-apoptotic protein SerpinB3, was selectively inhibited in terms of growth by some Au(iii)-DTC complexes.
Subject(s)
Antineoplastic Agents/chemistry , Carbamates/chemistry , Coordination Complexes/chemistry , Gold/chemistry , Proline/analogs & derivatives , Proline/chemistry , Antigens, Neoplasm/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Coordination Complexes/pharmacology , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Serpins/metabolismABSTRACT
In this paper, we focused on the analysis of the effects mediated by different cyclic dithiocarbamic ligands (DTC) on three classes of antiproliferative coordination compounds, namely, Ru(iii) complexes with the general formulae [Ru(DTC)3] and [Ru2(DTC)5]Cl, and the neutral Cu(ii) derivatives of the type [Cu(DTC)2]. In particular, we present the synthesis and characterization of a library of total 23 coordination compounds containing Ru(iii) or Cu(ii) as the biologically-active metal center and two or more dithiocarbamato (DTC) ligands derived from cyclic amines (aliphatic or aromatic). Several techniques including elemental analysis, X-ray crystallography, ESI-MS, 1H-NMR spectroscopy, FT-IR and UV-Vis spectrophotometry were used to characterize the compounds, which highlighted the different electronic behaviors generated by the substituents within the DTC moiety. Moreover, the synthesized compounds were tested for their stability in order to investigate their antiproliferative activity against 3 human cancer cell lines, namely, HeLa, HepG2 and HepG2/SB3. In particular, HepG2/SB3 was chosen for its aggressiveness due to upregulation of the anti-apoptotic protein SerpinB3. Finally, the most promising compounds are studied in terms of log P. Overall, the results reveal the drug-likeness of some of the derivatives of copper(ii) and ruthenium(iii).
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carbamates/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/pharmacology , Copper/chemistry , Ruthenium/chemistry , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Coordination Complexes/chemistry , Humans , Models, Molecular , Molecular ConformationABSTRACT
Since the discovery of cisplatin in the 1960s, other metal complexes have been investigated as potential antitumor agents to overcome the side-effects associated with the administration of the Pt-based drug. In line with our previous research, in this work we report the synthesis and characterization of mono- and dinuclear Ru(III) complexes with the pyrrolidinedithiocarbamate (PDT) ligand and the more sterically-hindered carbazole-dithiocarbamato ligand (CDT), to compare their properties (both at the chemical and antiproliferative level), in an attempt to assess a structure-activity rationale. Moreover, to overcome the scarce solubility under physiological conditions of the Ru(III)-dithiocarbamato compounds, the biocompatible copolymer Pluronic® F127 has been used, to encapsulate the metal derivatives in water-soluble micellar carriers. Finally, preliminary biological evaluations on CDT and PDT compounds along with their nanoformulations, open intriguing perspectives in anticancer chemotherapy. In particular, comparing the structure of the Ru(III) derivatives, the ionic dinuclear PDT complex shows an important cytotoxic action in comparison to its neutral counterparts. Moreover, the micellar carrier improves the overall activity of the encapsulated Ru(III)-PDT chemotherapeutics. On the other hand, the nanoformulation of the CDT derivatives allows us to solubilize both the 1:3 and the 2:5 complexes and to state their inactivity.
