Chloroquine-containing organoruthenium complexes are fast-acting multistage antimalarial agents

© Cambridge University Press 2016We report the pharmacological activity of organoruthenium complexes containing chloroquine (CQ) as a chelating ligand. The complexes displayed intraerythrocytic activity against CQ-sensitive 3D7 and CQ-resistant W2 strains of Plasmodium falciparum, with potency and selectivity indexes similar to those of CQ. Complexes displayed activity against all intraerythrocytic stages, but moderate activity against Plasmodium berghei liver stages. However, unlike CQ, organoruthenium complexes impaired gametocyte viability and exhibited fast parasiticidal activity against trophozoites for P. falciparum. This functional property results from the ability of complexes to quickly induce oxidative stress. The parasitaemia of P. berghei-infected mice was reduced by treatment with the complex. Our findings demonstrated that using chloroquine for the synthesis of organoruthenium complexes retains potency and selectivity while leading to an increase in the spectrum of action and parasite killing rate relative to CQ.This research was funded by FAPESB (grant PET0042/2013, Brazil) to M.B.P.S, FAPESP (grant 14/10516-7, Brazil) to A.A.B. and Fundação para a Ciência e Tecnologia (grant PTDC/SAU-MIC/117060/2010 Portugal) to M.P. A.A.B. and M.B.P.S. are recipients of senior fellowships by CNPq (Brazil)info:eu-repo/semantics/publishedVersio

Síntese de complexos semi-sanduíche n6-p-cimeno- Ru(II) contendo ligantes binitrogenados, interação com o DNA e potenciais atividades farmacológicas / Legna Andreina Colina Vegas

The synthesis, spectroscopic characterization, crystal structures and electrochemistry of π-arene piano-stool ruthenium (II) complexes with pyridine or derivatives as nitrogen donor ligands are described. A series of six organometallic compounds of formulae [RuCl(η6-p-cymene)(N∩N)]PF6 [N∩N=1,10’-phenantroline (phen), 4,7’-diphenil-1,10’-phenantroline (phphen), 2,2’-bipyridine (bipy), 5,5’-dimethyl-2,2’-bipyridine (mebipy), 4,4’-dimethoxi-2,2’-bipyridine (meobipy) and 4,4’-di-t-buthyl-2,2’-bipyridine (butbipy)]were synthesized and fully characterized. The solid state structures of the six complexes were determined by X-ray crystallography and their characterization was completed by FT-IR spectroscopy, molar conductivity and NMR studies (1H and 13C). Electrochemical experiments were performed by cyclic voltammetry to estimate the redox potential of the Ru(II)/Ru(III) couple and this potential does not vary significantly between the complexes. Additionally, spectroscopic titration with DNAct were done, to estimate interaction constants between the metal complex and this macromolecule. The values of the constants indicate a reversible interaction with DNA, which is in concordance with the literature.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)A síntese, caracterização espectroscópica, as estruturas cristalinas e electroquímica de complexos “piano stool” π-arenos de rutênio (II) com bipiridina ou seus derivados como ligantes doadores são descritos. Uma série de seis compostos organometálicos de fórmula [RuCl(η6-p-cymeno)(N∩N)]PF6 [N∩N = 1,10 '-fenantrolina (fen), 4,7'-difenil-1,10'-fenantrolina (fenilfen), 2,2'-bipiridina (bipy), 5,5'-dimetil-2,2'-bipiridina (mebipy), 4,4'-dimetoxi-2,2'-bipiridina (meobipy) e 4,4'-di-t-butil-2,2'-bipiridina (butbipy)] foram sintetizados e caracterizados. As estruturas no estado sólido de seis complexos foram determinadas por cristalografia de raios X e a sua caracterização foi completada por espectroscopia de absorção na região do IV, condutividade molar e espectroscopia de RMN (1H e 13 C). Experimentos electroquímicos foram realizados por voltametria cíclica para estimar o potencial redox do par Ru(II)/Ru(III), o qual não varia significativamente entre os complexos. Adicionalmente, foram feitas titulações espectroscópicas dos complexos com o DNA, para estimar constantes de interação entre os complexos metálicos e esta macromolécula, encontrando-se constantes de interação com valores que estão no intervalo para complexos metálicos já reportados na literatura com interações reversíveis

Cellular and sub-cellular Cu isotope fractionation in the human neuroblastoma SH-SY5Y cell line : proliferating versus neuron-like cells

Cu isotope fractionation was investigated in the human neuroblastoma SH-SY5Y cell line, in a proliferating/tumor phase (undifferentiated cells), and in a differentiated state (neuron-like cells), induced using retinoic acid (RA). The SH-SY5Y cell line displays genetic aberrations due to its cancerous origin, but differentiation drives the cell line towards phenotypes suitable for the research of neurological diseases (e.g., Alzheimer's disease or Parkinson's disease). Cellular Cu distribution was first explored by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging and, subsequently, Cu isotopic analysis was performed at cellular and sub-cellular levels via multi-collector inductively coupled plasma-mass spectrometry (MC-ICP-MS). The SH-SY5Y cells showed a re-distribution of intracellular Cu upon RA differentiation. Both undifferentiated and differentiated cells became systematically enriched in the light Cu-63 isotope with increasing intracellular Cu content. Differentiated neuron-like SH-SY5Y cells showed a heavier Cu isotopic composition (+0.3) than did the undifferentiated proliferating cells when exposed to Cu for 24h. However, after a longer exposure time (72h), no difference was observed between both cellular phenotypes. Mitochondrial fractions were enriched in the light Cu-63 isotope, compared to whole cells, for both undifferentiated and differentiated cells (no significant difference). The Cu isotopic composition of the remaining cell lysates was heavier than that of the whole cells and +0.2 heavier in the differentiated cells than in the undifferentiated cells. These results indicate that neuronal differentiation affects the Cu isotope fractionation accompanying Cu uptake in the cells, but this effect does not seem to be associated with the mitochondrial Cu pathway. Cu isotope fractionation can be an interesting tool for studying Cu metabolism at a (sub)-cellular level in functional neurons

Selective ablation of biological tissue and single cells on a glass substrate by controlling the laser energy density of nanosecond 193 nm laser radiation

This paper describes the possibility of controlling and reducing the laser energy density of nanosecond 193 nm laser radiation in order to selectively ablate biological material from a glass substrate for LA-ICP-MS bioimaging applications. Atomic force microscopy and optical profilometry were used to study the shape of single-shot craters in dried gelatin droplets, ablated at low energy (<500 mJ cm(-2)). These craters were characterized by straight walls and a 'flat bottom'. Based on the ablated volume per pulse and corresponding ablation depth, the ablation threshold of the dried gelatin material was estimated at 44 mJ cm(-2) by relying on the Beer model derived from the Beer-Lambert law. Three different glass substrates, i.e. a microscope slide and coverslip of soda-lime-silica (SLS) glass with a slightly different bulk elemental composition and a borosilicate glass coverslip, were ablated using laser energy densities ranging from 150-730 mJ cm(-2) and typical instrument settings applied during LA-ICP-MS bioimaging. The signal intensity of Si-29, a minor isotope of Si which is a major matrix component of the glass surface, was monitored as a measure of material removal and was used to estimate ablation thresholds for the three glass substrates at 262, 181 and 104 mJ cm(-2), respectively. As a proof-of-concept, kidney tissue mounted onto a SLS glass microscope slide substrate and MDA-MB-231 tumor cells seeded on a SLS glass coverslip were selectively ablated by controlling the laser energy density to ensure soft ablation of the glass substrate, but provide hard ablation of the biological material

Anti-Proliferative and Anti-Migration Activity of Arene–Ruthenium(II) Complexes with Azole Therapeutic Agents

The efficacy of organoruthenium complexes containing ergosterol biosynthesis inhibitors (CTZ: clotrimazole, KTZ: ketoconazole and FCZ: fluconazole) against tumor cells, and their interaction with important macro-biomolecules such as human serum albumin and DNA have been investigated here. Our experimental results indicated that these ruthenium(II) complexes present spontaneous electrostatic interactions with albumin, and act as minor groove binders with the DNA. The ability of these Ru(II)&#8315;azole complexes to inhibit the proliferation of selected human tumor and non-tumor cell lines was determined by MTT assay. Complexes [RuCl(CTZ)(&#951;6-p-cymene)(PPh3)]PF6 (3) and [RuCl(KTZ)(&#951;6-p-cymene)(PPh3)]PF6 (4) were shown to be between 3- and 40-fold more cytotoxic than the free ligands and the positive control cisplatin. Complex 3 was selected to continue studies on the triple negative breast tumor cell line MDA-MB-231, inducing morphological changes, loss of adhesion, inhibition of colony formation, and migration through Boyden chambers, cell cycle arrest in the sub-G1 phase, and a mechanism of cell death by apoptosis. All these interesting results show the potential of this class of organometallic Ru(II) complexes as an antiproliferative agent

Antiparasitic activity and ultrastructural alterations provoked by organoruthenium complexes against Leishmania amazonensis.

Four new organoruthenium complexes with formula [RuCl(?6-p-cymene)(?-FCZ)]2[Cl]2 (1), [RuCl(FCZ)(?6-p-cymene)(PPh3)]PF6 (2), [RuCl(CTZ)(?6-p-cymene)(PPh3)]PF6 (3) and [RuCl(KTZ)(?6-p-cymene)(PPh3)]PF6 (4) (where FCZ: 2-(2,4-difluorophenyl)-1,3-di(1H-1,2,4-triazol-1-yl)-2-propanol, CTZ: 1-[(2-chlorophenyl)-diphenylmethyl-1H-imidazole] and KTZ: cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine) were synthesized, characterized and evaluated as potential inhibitors for Leishmania amazonensis growth by widely reported methods. Complexes 3 and 4 displayed effective IC50 activities against Leishmania amazonensis promastigotes and intracellular amastigotes in the range of nanomolar concentration. Scanning and transmission electron microscopy analysis of Leishmania amazonensis promastigotes after treatment with 300 or 500 nM of complexes 3 and 4 for 48 h showed morphological alterations in the cell surface, a shortening of the flagellum, loss of mitochondrial matrix, disorganization of the kDNA and abnormal chromatin condensation. Thus, our strategy of incorporating a ruthenium atom into the structure of clinical drugs to improve their efficacy continues to demonstrate suitability for metallodrug discovery purposes

Copper(I)–Phosphine Polypyridyl Complexes: Synthesis, Characterization, DNA/HSA Binding Study, and Antiproliferative Activity

A series of copper­(I)–phosphine polypyridyl complexes have been investigated as potential antitumor agents. The complexes [Cu­(PPh₃)₂­dpq]­NO₃ (<b>2</b>), [Cu­(PPh₃)₂­dppz]­NO₃ (<b>3</b>), [Cu­(PPh₃)₂­dppa]­NO₃ (<b>4</b>), and [Cu­(PPh₃)₂­dppme]­NO₃ (<b>5</b>) were synthesized by the reaction of [Cu­(PPh₃)₂NO₃] with the respective planar ligand under mild conditions. These copper complexes were fully characterized by elemental analysis, molar conductivity, FAB-MS, and NMR, UV–vis, and IR spectroscopies. Interactions between these copper­(I)–phosphine polypyridyl complexes and DNA have been investigated using various spectroscopic techniques and analytical methods, such as UV–vis titrations, thermal denaturation, circular dichroism, viscosity measurements, gel electrophoresis, and competitive fluorescent intercalator displacement assays. The results of our studies suggest that these copper­(I) complexes interact with DNA in an intercalative way. Furthermore, their high protein binding affinities toward human serum albumin were determined by fluorescence studies. Additionally, cytotoxicity analyses of all complexes against several tumor cell lines (human breast, MCF-7; human lung, A549; and human prostate, DU-145) and non-tumor cell lines (Chinese hamster lung, V79-4; and human lung, MRC-5) were performed. The results revealed that copper­(I)–phosphine polypyridyl complexes are more cytotoxic than the corresponding planar ligand and also showed to be more active than cisplatin. A good correlation was observed between the cytostatic activity and lipophilicity of the copper­(I) complexes studied here