Group 11 complexes with amino acid derivatives: Synthesis and antitumoral studies

• Several group 11 metal complexes with modified amino acid esters have been prepared.
• Most of these derivatives are highly cytotoxic.
• The gold complexes are the most active of all the series.
• The use of PPh2pyridine instead of PPh3 as auxiliary ligand produces more cytotoxic agents.
• The mechanism of cell death has been studied showing that it is mainly apoptotic.

Gold(I), gold(III), silver(I) and copper(I) complexes with modified amino acid esters and phosphine ligands have been prepared in order to test their cytotoxic activity. Two different phosphine fragments, PPh3 and PPh2py (py = pyridine), have been used. The amino acid esters have been modified by introducing an aromatic amine as pyridine that coordinates metal fragments through the nitrogen atom, giving complexes of the type [M(L)(PR3)]+ or [AuCl3(L)] (L = l-valine-N-(4-pyridylcarbonyl) methyl ester (L1), l-alanine-N-(4-pyridylcarbonyl) methyl ester (L2), l-phenylalanine-N-(4-pyridylcarbonyl) methyl-ester) (L3); M = Au(I), Ag(I), Cu(I), PR3 = PPh3, PPh2py). The in vitro cytotoxic activity of metal complexes was tested against four tumor human cell lines and one tumor mouse cell line. A metabolic activity test (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide, MTT) was used and IC50 values were compared with those obtained for cisplatin. Several complexes displayed significant cytotoxic activities. In order to determine whether antiproliferation and cell death are associated with apoptosis, NIH-3T3 cells were exposed to five selected complexes (Annexin V + FITC, PI) and analyzed by flow cytometry. These experiments showed that the mechanism by which the complexes inhibit cell proliferation inducing cell death in NIH-3T3 cells is mainly apoptotic.

Group 11 metal complexes with pyridine modified amino acid esters and phosphine ligands have been prepared. The complexes display significant cytotoxic activity in several tumor cell lines. Flow cytometry experiments showed that the mechanism by which the complexes inhibit cell proliferation, inducing cell death is mainly apoptotic.Figure optionsDownload as PowerPoint slide