Antineoplastic Evaluation of Two Mixed Chelate Copper Complexes (Casiopeínas®) in HCT-15 Xenograft Model

Abstract

Casiopeínas<sup>®</sup> is a family of copper complexes with the general formulae [Cu(N-N)(N-O)]NO<sub>3</sub> and [Cu(N-N)(O-O)]NO<sub>3</sub>; where N-N = substituted aromatic diimine (2,2’-bipyridine (<em>bipy</em>) or 1,10-phenanthroline (<em>phen</em>)); N-O = α-aminoacidate or a peptide; and O-O = acetylacetonate (<em>acac</em>) or salicylaldehydate. These compounds have shown antiproliferative activity in vitro and antitumor activity in several mouse models with promissory results. Efforts have been done in order to understand the role played by ligands in the biological activity. With the aim of finding out the effect of secondary ligand (N-O or O-O), two of the most active complexes <em>in vitro</em> assays were selected to perform in vivo study on HCT-15 colon adenocarcinoma xenograft model. Both complexes, [Cu(3,4,7,8-tetramethyl-1,10-phen anthroline)(glycinato)]NO<sub>3</sub> (<strong>1</strong>) and [Cu(3,4,7,8-tetramethyl-1,10-phenanthroline)(acetylacetonato)]NO<sub>3</sub> (<strong>2</strong>) share the same diimine ligand and the secondary ligand changes from glycinate (<em>gly</em>) to <em>acac</em>. Results show that 2 is effective to reduce tumor size but <strong>1</strong> does not achieve the values required according to protocols, revealing an important difference between compounds attributable to change of ligand from <em>gly</em> to <em>acac</em>.

Synthesis and Investigations of the Antitumor Effects of First-Row Transition Metal(II) Complexes Supported by Two Fluorinated and Non-Fluorinated β-Diketonates

“…In fact, β-diketones are known to form complexes with almost every metal, and they have been used as supporting ligands for Ti(IV)- [27,28], Ru(II)- [29][30][31][32][33][34][35], Pd(II)- [36] and Ptbased anticancer agents [37][38][39][40][41][42][43]. The β-diketones were used as supporting ligands for heteroleptic Cu(II) complexes, such as Casiopeinas ® -like compounds (Cas III) [44][45][46][47][48][49], and analogous heteroleptic complexes with β-diketones and N,N'-chelating aromatic ligands (2,2-bipyridine, 1,10-phenanthroline, and related substituted derivatives) have been studied for their potential antitumor activities [50][51][52][53][54]. The most studied metal-based β-diketone derivatives are the metal-based curcuminoids derivatives, and many of these have been reported and evaluated as anticancer agents [55][56][57][58][59][60][61][62][63].…”

Intermediate Detection in the Casiopeina–Cysteine Interaction Ending in the Disulfide Bond Formation and Copper Reduction

“…The Casiopeina activity goes along with the cytotoxic effects, such as the generation of reactive oxygen species (ROS) [ 21 , 22 ], which can damage cellular components through oxidation and alter the oxidation-reduction balance cell or interfere with the mechanisms of cellular signaling related to the redox state [ 23 ]. There are reports about the antiproliferative and antineoplastic activities over murine and xenografted human tumors [ 24 , 25 ]. On the other hand, survival was evaluated in murine models: L1210 (leukemia), S180 (sarcoma), and B16 (melanoma) [ 26 ].…”

1H -NMR Metabolomics Study of the Effect of Cisplatin and Casiopeina IIgly on MDA-MB-231 Breast Tumor Cells

“…The Casiopeinas® are coordination compounds which have copper as their central atom, they substitute bipyridine or phenanthroline as the primary ligand and glycinate or acetylacetonate as the secondary ligand ( Ruiz-Azuara, 1990 ; Ruiz-Azuara, 1992 ; Ruiz-Azuara, 1996 ; Ruiz-Azuara, 1997 ). These compounds have been shown to be biologically active in diverse tumor cells in vitro as well as in vivo ( Trejo et al, 2005 ; Carvallo-Chaigneau et al, 2008 ; Bravo-Gómez et al, 2009 ; Ruiz-Azuara and Bravo, 2010 ; Bravo et al, 2013 ), and it is important to mention that the Casiopeinas® present a selectivity to tumor cells as their effect over healthy cells is low ( Espinal-Enríquez et al, 2016 ; García-Ramos et al, 2017 ).…”