Complexes of Pd(II) and Pt(II) with 9-aminoacridine: reactions with DNA and study of their antiproliferative activity

Four new metal complexes {M = Pd(II) or Pt(II)} containing the ligand 9-aminoacridine (9AA) were prepared. The compounds were characterized by FT-IR and 1H, 13C, and 195Pt NMR spectroscopies. Crystal structure of the palladium complex of formulae [Pd(9AA)(μ-Cl)]2 · 2DMF was determined by X-ray diffraction. Two 9-acridine molecules in the imine form bind symmetrically to the metal ions in a bidentate fashion through the imine nitrogen atom and the C(1) atom of the aminoacridine closing a new five-membered ring. By reaction with phosphine or pyridine, the Cl bridges broke and compounds with general formulae [Pd(9AA)Cl(L)] (where L = PPh3 or py) were formed. A mononuclear complex of platinum of formulae [Pt(9AA)Cl(DMSO)] was also obtained by direct reaction of 9-aminoacridine and the complex [PtCl2(DMSO)2]. The capacity of the compounds to modify the secondary and tertiary structures of DNA was evaluated by means of circular dichroism and electrophoretic mobility. Both palladium and platinum compounds proved active in the modification of both the secondary and tertiary DNA structures. AFM images showed noticeable modifications of the morphology of the plasmid pBR322 DNA by the compounds probably due to the intercalation of the complexes between base pairs of the DNA molecule. Finally, the palladium complex was tested for antiproliferative activity against three different human tumor cell lines. The results suggest that the palladium complex of formula [Pd(9AA)(μ-Cl)]2 has significant antiproliferative activity, although it is less active than cisplatin

Synthesis, characterization and antiproliferative activity on mesothelioma cell lines of bis(carboxylato)platinum(IV) complexes based on picoplatin

The synthesis and characterization of a series of picoplatin-based ( picoplatin = [PtCl2(mpy)(NH3)], mpy = 2-methylpyridine), Pt(IV) complexes with axial carboxylato ligands of increasing length are reported. The synthesis is based on the oxidation with hydrogen peroxide of picoplatin to give the cis,cis,trans- [PtCl2(mpy)(NH3)(OH)2] intermediate and then its transformation into the dicarboxylato complexes cis, cis,trans-[PtCl2(mpy)(NH3)(RCOO)2] (R = CH3(CH2)n, n = 0-4) with the corresponding anhydride. Pt(IV) complexes with n = 0-2 were selected to be tested on four malignant pleural mesothelioma (MPM) cell lines, on human mesothelial cells (HMC), and on the cisplatin-sensitive ovarian A2780 cell line along with cisplatin as a metallo-drug reference. In general, the longer the axial chain, the more cytotoxic and selective the Pt(IV) complex is. Pt(IV) analogs show good activity on the MPM cell lines, approaching or in some case bypassing that of cisplatin and represent quite promising drug candidates for the treatment of tumors whose chemoresistance is mainly based on glutathione overexpression, such as MPM

Influence of PPh3 moiety in the anticancer activity of new organometallic ruthenium complexes

The effect of the PPh3 group in the antitumor activity of some new organometallic Ruthenium (II) complexes has been investigated. Several complexes of the type [Ru(II)(Cl)(PPh3)(Lig-N)], [Ru(II)(Cl)2(Lig-N)] (where Lig-N=pyridine derivate) and [Ru(II)(Cl)(PPh3)2], have been synthesized and characterized, and an important increment of the antitumor activity and cytotoxicity of the complexes due to the presence of PPh3 moiety has been demonstrated, affording IC50 values of 5.2 μM in HL-60 tumour cell lines. Atomic Force Microscopy, Circular Dichroism and Electrophoresis experiments have proved that these complexes can bind DNA resulting in a distortion of both secondary and tertiary structures. Ethidium bromide displacement Fluorescence Spectroscopy studies and Viscosity measurements support that the presence of PPh3 group induces intercalation interactions with DNA. Indeed, crystallographic analysis, suggest that intra-molecular π-π interactions could be involved in the intercalation within DNA base pairs. Furthermore, HPLC-MS studies have confirmed a strong interaction between Ruthenium complexes and proteins (Ubiquitin and Potato Carboxypeptidase Inhibitor -PCI-) including slower kinetic due to the presence of PPh3 moiety, which could have an important role in detoxification mechanism and others. Finally, Ion Mobility Mass Spectrometry (IMMS) experiments have proved that there is no change in the structural conformation of the proteins owing to their bonding to Ruthenium complexes. This seems particularly important in the case of PCI, that may be a suitable candidate for vehiculizing these complexes in a selective manner into tumour cells. In agreement with these results, further investigations should be carried out to clarify either there is a favoured binding to DNA or to specific proteins, thus to elucidate their main biological target

New iron(II) cyclopentadienyl derivative complexes: synthesis and antitumor activity against human leukemia cancer cells

A new family of 'FeII(h5-C5H5)' half sandwich compounds bearing a N-heteroaromatic ligand coordinated to the iron center by a nitrile functional group has been synthesized and fully characterized by NMR and UVeVis spectroscopy. X-ray analysis of single crystal was achieved for complexes 1 and 3, which crystallized in the monoclinic P21/c and monoclinic P21/n space groups, respectively. Studies of interaction of these five new complexes with plasmid pBR322 DNA by atomic force microscopy showed very strong and different types of interaction. Antiproliferative tests were examined on human leukemia cancer cells (HL-60) using the MTT assay, and the IC50 values revealed excellent antiproliferative activity compared to cisplatin

Integrin-targeted delivery into cancer cells of a Pt(IV) pro-drug through conjugation to RGD-containing peptides

Conjugates of a Pt(IV) derivative of picoplatin with monomeric (Ptc(RGDfK), 5) and tetrameric (PtRAFT-{c(RGDfK)}4, 6) RGD-containing peptides were synthesized with the aim of exploiting their selectivity and high affinity for αVβ3 and αVβ5 integrins for targeted delivery of this anticancer metallodrug to tumor cells overexpressing these receptors. Solid- and solution-phase approaches in combination with click chemistry were used for the preparation of the conjugates, which were characterized by high resolution ESI MS and NMR. αVβ3 and αVβ5 integrin expression was evaluated in a broad panel of human cancer and nonmalignant cells. SK-MEL-28 melanoma cells were selected based on the high expression levels of both integrins, while CAPAN-1 pancreatic cancer cells and 1BR3G fibroblasts were selected as the negative control. Internalization experiments revealed a good correlation between integrin expression and the celular uptake of the corresponding fluorescein-labeled peptides and that the internalization capacity of the tetrameric RGD-containing peptide was considerably higher than that of the monomeric one. Cytotoxic experiments indicated that the antitumor activity of picoplatin in melanoma cells was increased by 2.6-fold when its Pt(IV) derivative was conjugated to c(RGDfK) (IC50 = 12.8 ± 2.1 μM) and by 20-fold when conjugated to RAFT-{c(RGDfK)}4 (IC50 = 1.7 ± 0.6 μM). In contrast, the cytotoxicity of the conjugates was inhibited in control cells lacking αVβ3 and αVβ5 integrin expression. Finally, cellular uptake studies by ICP-MS confirmed a good correlation between the levels of expression of integrins, intracellular platinum accumulation and antitumor activity. Indeed, accumulation and cytotoxicity were much higher in SK-MEL-28 cells than in CAPAN-1, being particularly higher in the case of the tetrameric conjugate. The overall results highlight that the great ability of RAFT-{c(RGDfK)}4 to bind to and to be internalized by integrins overexpressed in SK-MEL-28 cells results in higher accumulation of the Pt(IV) complex, leading to a high antitumor activity. These studies provide new insights into the potential of targeting αVβ3 and αVβ5 integrins with Pt(IV) anticancer pro-drugs conjugated to tumor-targeting devices based on RGDcontaining peptides, particularly on how multivalency can improve both the selectivity and potency of such metallodrugs by increasing cellular accumulation in tumor tissues

Hydroxyl Groups Induce Bioactivity in Silica/Chitosan Aerogels Designed for Bone Tissue Engineering. In Vitro Model for the Assessment of Osteoblasts Behavior

Silica (SiO2)/chitosan (CS) composite aerogels are bioactive when they are submerged in simulated body fluid (SBF), causing the formation of bone-like hydroxyapatite (HAp) layer. Silica-based hybrid aerogels improve the elastic behavior, and the combined CS modifies the network entanglement as a crosslinking biopolymer. Tetraethoxysilane (TEOS)/CS is used as network precursors by employing a sol-gel method assisted with high power ultrasound (600 W). Upon gelation and aging, gels are dried in supercritical CO2 to obtain monoliths. Thermograms provide information about the condensation of the remaining hydroxyl groups (400-700 degrees C). This step permits the evaluation of the hydroxyl group's content of 2 to 5 OH nm(-2). The formed Si-OH groups act as the inductor of apatite crystal nucleation in SBF. The N-2 physisorption isotherms show a hysteresis loop of type H3, characteristic to good interconnected porosity, which facilitates both the bioactivity and the adhesion of osteoblasts cells. After two weeks of immersion in SBF, a layer of HAp microcrystals develops on the surface with a stoichiometric Ca/P molar ratio of 1.67 with spherulite morphology and uniform sizes of 6 mu m. This fact asserts the bioactive behavior of these hybrid aerogels. Osteoblasts are cultured on the selected samples and immunolabeled for cytoskeletal and focal adhesion expression related to scaffold nanostructure and composition. The initial osteoconductive response observes points to a great potential of tissue engineering for the designed composite aerogels

Chitosan-GPTMS-Silica Hybrid Mesoporous Aerogels for Bone Tissue Engineering

This study introduces a new synthesis route for obtaining homogeneous chitosan (CS)-silica hybrid aerogels with CS contents up to 10 wt%, using 3-glycidoxypropyl trimethoxysilane (GPTMS) as coupling agent, for tissue engineering applications. Aerogels were obtained using the sol-gel process followed by CO2 supercritical drying, resulting in samples with bulk densities ranging from 0.17 g/cm(3) to 0.38 g/cm(3). The textural analysis by N-2-physisorption revealed an interconnected mesopore network with decreasing specific surface areas (1230-700 m(2)/g) and pore sizes (11.1-8.7 nm) by increasing GPTMS content (2-4 molar ratio GPTMS:CS monomer). In addition, samples exhibited extremely fast swelling by spontaneous capillary imbibition in PBS solution, presenting swelling capacities from 1.75 to 3.75. The formation of a covalent crosslinked hybrid structure was suggested by FTIR and confirmed by an increase of four hundred fold or more in the compressive strength up to 96 MPa. Instead, samples synthesized without GPTMS fractured at only 0.10-0.26 MPa, revealing a week structure consisted in interpenetrated polymer networks. The aerogels presented bioactivity in simulated body fluid (SBF), as confirmed by the in vitro formation of hydroxyapatite (HAp) layer with crystal size of approximately 2 mu m size in diameter. In vitro studies revealed also non cytotoxic effect on HOB(R) osteoblasts and also a mechanosensitive response. Additionally, control cells grown on glass developed scarce or no stress fibers, while cells grown on hybrid samples showed a significant (p < 0.05) increase in well-developed stress fibers and mature focal adhesion complexes

Verbeia: Journal of english and spanish studies

Verbeia nace con la finalidad de contagiarnos con la pasión de la Filología. Durante este año hemos crecido, nuestro Comité Científico aumenta y con él las esperanzas de estabilidad. Todos sabemos lo que cuesta llegar hasta aquí, y hoy llegamos con artículos escritos por profesores e investigadores de distintas universidades del planeta

Solid-phase synthesis and DNA binding studies of dichloroplatinum(II) conjugates of dicarba analogues of octreotide as a new anticancer drugs

The first dichloroplatinum(II) conjugates of dicarba analogues of octreotide , which is expected to act as a"tumour-targeting device", have been efficiently synthesized following a stepwise solid-phase approach; these compounds emulate the mechanism of cisplatin since they form a 1,2-intrastrand cross-link with two consecutive guanines of an oligonucleotide