New palladium and platinum complexes with bioactive 3,5-diacetyl-1,2,4-triazol bis(4-cyclohexyl thiosemicarbazone) ligand: chemistry, antiproliferative activity and preliminary toxicity studies

Abstract

The preparation and characterization of the new 3,5-diacetyl-1,2,4-triazol bis(4-cyclohexyl thiosemicarbazone) ligand, H(5)L(1), is described. Treatment of H(5)L(1) with K(2)PtCl(4) gave the dinuclear complex [Pt(H(3)L(1))](2), 1, but using MCl(2)(PPh(3))(2) where M = Pd or Pt, mononuclear complexes 2 and 3, of general formula [M(H(3)L(1))PPh(3)], were obtained. Subsequent reaction of the [Pd(H(3)L(1))PPh(3)] complex with PdCl(2)(PPh(3))(2) yielded a new dinuclear complex [(PPh(3))Pd(H(2)L(1))PdCl], 4. All compounds have been characterized by elemental analysis and FAB(+) spectrometry and by IR and NMR spectroscopy. The molecular structures of mononuclear complexes 2 and 3 and dinuclear complex 4 have been determined by X-ray crystallography. The new compounds synthesized have been evaluated for antiproliferative activity in vitro against NCI-H460, HepG2, MCF-7, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that the H(5)L(1) ligand and [Pt(H(3)L(1))](2), complex 1, may be endowed with important cytotoxic properties since they are capable of not only circumventing cisplatin resistance in A2780cisR but also exhibit antiproliferative activity in NCI-H460. The interactions of these compounds with calf thymus DNA were investigated by UV-vis absorption and a nephrotoxic study, in LLC-PK1 cells, has also been carried out.

Supramolecular interaction of transition metal complexes with albumins and DNA: Spectroscopic methods of estimation of binding parameters

“…[100,101] Due to this fact, the antitumor properties of a large number of palladium(II) complexes are investigated. [102][103][104][105] Ruthenium complexes with fluoroquinolones are actively applied in clinical practice since they possess a high pharmacological activity, low toxicity, and interact with many biopolymers, DNA first of all. These peculiarities of ruthenium complexes can be partly explained by the ability of ruthenium to imitate iron in biological media, as well as by its rich coordination chemistry from the standpoint of available oxidative states, hydrolysis rates, and photochemistry.…”

Iron(III) and nickel(II) complexes of tetradentate thiosemicarbazones: Synthesis, structure, cytotoxicity, and lipophilicity

“…Thiosemicarbazones are multidentate ligands having three nitrogen atoms. Since the drug potentials of platinum(II), palladium(II), and copper(II) complexes of some thiosemicarbazones, these metal ions have been commonly used to obtain the complexes of various thiosemicarbazone ligands. Some transition metal ions such as iron(III) and zinc(II) have been also examined to increase the biological activity of bidentate and tridentate thiosemicarbazones …”

Cytotoxic effect of palladium (II) inclusion compounds in beta-cyclodextrin

“…En la actualidad, se están ensayando numerosos complejos de paladio (II) (2) y tiosemicarbazonas (3) con actividad promisoria contra líneas celulares de tumores, debido a su notable actividad citotóxica y menores efectos secundarios en comparación con otros compuestos anticancerígenos de metales pesados (4)(5)(6). Además de su potencial actividad antineoplásica, tienen mayor solubilidad y menos efectos secundarios que el cisplatino (7)(8)(9).…”

“…Debido a sus propiedades farmacológicas, la síntesis de complejos con metales de transición y ligandos como la tiosemicarbazona suscitan un gran interés (8). Se han propuesto varios mecanismos para explicar la acción antitumoral de estos complejos, entre los cuales está la inhibición de la biosíntesis del ADN mediante el bloqueo de la enzima ribonucleótido reductasa, esencial en la conversión de ribonucleótidos en desoxirribonucleótidos, y su acción como agente intercalado entre las bases de pirimidina y de guanina del ADN, lo cual induce cambios en la conformación de la doble hélice y conduce a la muerte celular (5,7,20,21), y al bloqueo de la división de las células cancerosas (13).…”