Abstract
Two new thiosemicarbazone ligands, 2-propionylthiazole ethylthiosemicarbazone (PTZ-ETSC), and 2-propionylthiazole tert-butylthiosemicarbazone (PTZ-tBTSC), along with their two copper(II) complexes, [Cu(PTZ-ETSC)Cl] and [Cu(PTZ-tBTSC)Cl], are reported here for the first time. Once characterized by NMR and MS, these mono-anionic tridentate ligands were reacted with Cu2+ to form the square planar metal complexes [Cu(PTZ-ETSC)Cl] and [Cu(PTZ-tBTSC)Cl]. The x-ray crystal structure of the [Cu(PTZ-tBTSC)Cl] complex shows that the complex adopts a square planar arrangement around the copper(II) ion, but forms a sulfur-bridged dimer in the solid state. Both of the copper complexes displayed strong inhibition of human topoisomerase IIα at activities between 2-4 μM for [Cu(PTZ-ETSC)Cl], and between 8-10 μM for the [Cu(PTZ-tBTSC)Cl] complex. The EC50 values for the MDA-MB-231 breast cancer cell line were 82.6 μM for (PTZ-ETSC), 17.9 μM for [Cu(PTZ- ETSC)Cl], 97.8 μM for (PTZ-tBTSC), and 1.41 μM for [Cu(PTZ-tBTSC)Cl]. The EC50 values for the MCF7 breast cancer cell lines were 9.36 μM for (PTZ-ETSC), 0.13 μM for [Cu(PTZ-ETSC)Cl], 0.333 μM for (PTZ-tBTSC), and 0.093 μM for [Cu(PTZ-tBTSC)Cl].
Highlights
Thiosemicarbazones are exceptionally versatile multidentate ligands that coordinate to many transition metals with hundreds of papers in the literature discussing their biological activities, their analytical uses, and their ability to coordinate transition metal ions in a variety of oxidation states and geometries [1] [2] [3] [4] [5]
A specific subset of tridentate thiosemicarbazone ligands that have been referred to as α-(N)-heterocyclic thiosemicarbazones have extremely powerful anti-proliferative properties against a wide variety of microbes and cancer cells [8] [9] [10]. Some of these α-(N)-heterocyclic thiosemicarbazones, such as Triapine®, have potent activity against the enzyme ribonucleotide reductase which catalyzes the conversion of ribonucleotides into deoxyribonucleotides, providing the precursors required for DNA synthesis when a cell is dividing [11] [12] [13]
These ligands have some solubility in polar organic solvents such as methanol, ethanol, and isopropanol, and are more soluble in acetone and DMSO; but they are not appreciably soluble in water. These ligands show evidence of two conformers in solution at equilibrium at room temperature as seen by 13 MHz (1H) NMR. We have shown this type of equilibrium to be between an intramolecular hydrogen-bonded (HB) form and a non-hydrogen bonded (NHB) form for the analogous ligands ATZ-ETSC and ATZ-tBTSC, which has been recently published [25]
Summary
Thiosemicarbazones are exceptionally versatile multidentate ligands that coordinate to many transition metals with hundreds of papers in the literature discussing their biological activities, their analytical uses, and their ability to coordinate transition metal ions in a variety of oxidation states and geometries [1] [2] [3] [4] [5]. A specific subset of tridentate thiosemicarbazone ligands that have been referred to as α-(N)-heterocyclic thiosemicarbazones have extremely powerful anti-proliferative properties against a wide variety of microbes and cancer cells [8] [9] [10] Some of these α-(N)-heterocyclic thiosemicarbazones, such as Triapine®, have potent activity against the enzyme ribonucleotide reductase which catalyzes the conversion of ribonucleotides into deoxyribonucleotides, providing the precursors required for DNA synthesis when a cell is dividing [11] [12] [13]. Literature shows that the copper complexes of several series of tridentate mono-anionic α-(N)-heterocyclic thiosemicarbazones are known to exhibit greater antineoplastic activity and work by an entirely different mechanism than the ligands themselves [18] [19] [20]
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