Reactivity of dinuclear copper(II) complexes towards melanoma cells: Correlation with its stability, tyrosinase mimicking and nuclease activity

Abstract

In this work, the influence of two new dinuclear copper(II) complexes in the viability of melanoma cells (B16F10 and TM1MNG3) was investigated, with the aim of verifying possible correlations between their cytotoxicity and their structure. One of the complexes had a polydentate dinucleating amine-imine ligand (complex 2), and the other a tridentate imine and a diamine-bridging ligand (complex 4). The analogous mononuclear copper(II) species (complexes 1 and 3, respectively) were also prepared for comparative studies. Crystal structure determination of complex 2 indicated a square-based pyramidal geometry around each copper, coordinated to three N atoms from the ligand and the remaining sites being occupied by either solvent molecules or counter-ions. Complex 4 has a tetragonal geometry. Interactions of these complexes with human albumin protein (HSA) allowed an estimation of their relative stabilities. Complementary studies of their reactivity towards DNA indicated that all of them are able of causing significant oxidative damage, with single and double strand cleavages, in the presence of hydrogen peroxide. However, nuclease activity of the dinuclear species was very similar and much higher than that of the corresponding mononuclear compounds. Although complex 2, with a more flexible structure, exhibits a much higher tyrosinase activity than complex 4, having a more rigid environment around the metal ion, both complexes showed comparable cytotoxicity towards melanoma cells. Corresponding mononuclear complexes showed to be remarkably less reactive as tyrosinase mimics as well as cytotoxic agents. Moreover, the dinuclear complexes showed higher cytotoxicity towards more melanogenic cells. The obtained results indicated that the structure of these species is decisive for its activity towards the malignant tumor cells tested.

A new strategy for improving cytotoxicity of a copper complex toward metastatic melanoma cells unveiled by EPR spectroscopy

“…In contrast to compound 1 HYSCORE spectrum of compound 2 shows elongated cross peaks appearing at low frequency range [±0.5, +3.5], [±3.5, +0.5], [±2.5, +0.5], and [±0.5, +2.5] MHz, which correspond to the hyperne A N xyz = 1.5, 1.7, 1.7 MHz (A N iso ∼ 1.6 MHz), a nuclear quadrupole coupling e 2 Qq/h = 1 MHz, and an asymmetry parameter, h, of 0.85. Such values are typical for remote 14 N atoms in metal ion coordinated imidazoles reported by Mims and Peisach. 24 This together with observed in CW super-hyperne splitting allow us to assign these transitions to remote nitrogen of triazole ligand N6 or N7 (Fig.…”

“…12 Here, we report a new approach for selective cytotoxicity towards metastatic melanoma cells through a surprising dimerization of an oxindolimine copper(II) complex immobilized on the surface of modied Polyhedral Oligomeric Silsesquioxane (POSS) nanoparticles, as demonstrated by Electron Paramagnetic Resonance (EPR) spectroscopy. At rst, the idea was to extend the previous toxicity studies of imine copper(II) complexes with signicant antiproliferative activity already observed toward human neuroblastoma cells (SH-SY5Y), 13 and melanoma cells 14 (murine B16F10 and human TM1MNG3).…”

Avaliação da potencialidade e dos mecanismos de ação de complexos dinucleares de cobre como agentes terapêuticos antitumorais

“…Este complexo foi sintetizado e caracterizado anteriormente, conforme já publicado [30]. A formação da imina se dá pela reação de condensação entre 2-(acetil)piridina e histamina, seguida pela sua metalação, formando um sólido verde.…”

“…Canaletas: 1Kb marcador; DNA, DNA plasmidial (36ng/L); H 2 O 2 , DNA + H 2 O 2 (125µM); As concentrações de CuL, e os tempos de incubação estão indicadas no gel. (B) Razão da Forma II/Forma I do DNA determinado das bandas do gel de eletroforese na parte[30]. (A) Gel de agarose do plasmídio de DNA pBluescript II KS(+/-), incubado com o complexo [Cu 2 (apyhist) 2 dpam] 4+ (2) por 10, 20 e 40 min, com peróxido de hidrogênio.…”

“…Canaletas: 1Kb marcador; DNA, DNA plasmidial (36ng/L); H 2 O 2 , DNA + H 2 O 2 (125µM); As concentrações de CuL, e os tempos de incubação estão indicadas no gel. (B) Razão da Forma II/Forma I do DNA determinado das bandas do gel de eletroforese na parte (A)[30].Dentre os complexos estudados nestes ensaios e os anteriores podemos estabelecer uma ordem de reatividade para a capacidade dos vários complexos de clivar a dupla hélice do DNA. Em ordem decrescente de reatividade temos: complexo (2) capaz de clivar a dupla fita, porém com a necessidade de agente redox; complexo (5) com valores de razão de clivagem significativo nas concentrações 50 μM e pequena reatividade mesmo sem a adição de peróxido de hidrogênio; complexo (4) com boa reatividade e início de clivagem de concentração 25 μM, seguido do complexo (3) com reatividade razoável, o composto (que teve uma reatividade muito pouco significativa, e o composto (1) sem reatividade nas concentrações avaliadas, estudado anteriormente.…”