RESUMO
In this study, we present the synthesis, characterization and in vitro cytotoxicity of six organometallic [Ru(II)(η6-p-cymene)(N,N)Cl]Cl, [Rh(III)(η5-C5Me5)(N,N)Cl]Cl and [Re(I)(CO)3(N,N)Cl] complexes, in which the (N,N) ligands are sterane-based 2,2'-bipyridine derivatives (4-Me-bpy-St-OH, 4-Ph-bpy-St-OH). The solution chemical behavior of the ligands and the complexes was explored by UV-visible spectrophotometry and 1H NMR spectroscopy. The ligands and their Re(I) complexes are neutral at pH = 7.40; this contributes to their highly lipophilic character (log D7.40 > +3). The Ru(II) and Rh(III) half-sandwich complexes are much more hydrophilic, and this property is greatly affected by the actual chloride ion content of the medium. The half-sandwich Ru and Rh complexes are highly stable in 30% (v/v) DMSO/water (<5% dissociation at pH = 7.40); this is further increased in water. The Rh(III)(η5-C5Me5) complexes were characterized by higher water/chloride exchange and pKa constants compared to their Ru(II)(η6-p-cymene) counterparts. The Re(I)(CO)3 complexes are also stable in solution over a wide pH range (2-12) without the release of the bidentate ligand; only the chlorido co-ligand can be replaced with OH- at higher pH values. A comprehensive discussion of the binding affinity of the half-sandwich Ru(II) and Rh(III) complexes toward human serum albumin and calf-thymus DNA is also provided. The Ru(II)(η6-p-cymene) complexes interact with human serum albumin via intermolecular forces, while for the Rh(III)(η5-C5Me5) complexes the coordinative binding mode is suggested as well. They are also able to interact with calf-thymus DNA, most likely via the coordination of the guanine nitrogen. The Ru(II)(η6-p-cymene) complexes were found to be the most promising among the tested compounds as they exhibited moderate-to-strong cytotoxic activity (IC50 = 3-11 µM) in LNCaP as well as in PC3 prostate cells in an androgen receptor-independent manner. They were also significantly cytotoxic in breast and colon adenocarcinoma cancer cell lines and showed good selectivity for cancer cells.
Assuntos
Adenocarcinoma , Antineoplásicos , Neoplasias do Colo , Complexos de Coordenação , Cimenos , Compostos Organometálicos , Rutênio , Humanos , Complexos de Coordenação/química , Linhagem Celular Tumoral , Ligantes , Cloretos/química , Antineoplásicos/química , DNA/química , Albumina Sérica Humana , Água , Rutênio/farmacologia , Rutênio/química , Compostos Organometálicos/farmacologia , Compostos Organometálicos/químicaRESUMO
S-isoalkyl derivatives of thiosalicylic acid (isopropyl-(L1), isobutyl-(L2) and isoamyl-(L3)) were selected in order to investigate the binding interaction with the human serum albumin (HSA) using different spectroscopic methods and molecular docking simulation. Association constants and number of binding sites were used to analyze the quenching mechanism. The experimental results showed that the fluorescence quenching of HSA by L1, L2 and L3 occurs because of static quenching and that binding processes were spontaneous, with the leading forces in bonding by hydrogen bonding, hydrophobic interactions, and electrostatic interactions. Fluorescence spectroscopy, UV-Vis spectroscopy and synchronous fluorescence spectroscopy showed that ligands (L1, L2 and L3) can bind to HSA and that the binding of ligands induced some microenvironmental and conformational changes in HSA. The calculated distance between the donor and the acceptor according to fiFörster's theory confirms the energy transfer efficiency between the acceptor and HSA. Results of site marker competitive experiments showed that the tested compounds bind to HSA in domain IIA (Site I). Molecular dynamics and docking calculations demonstrated that L3 binds to the Sudlow site I of HSA with lower values of binding energies compared to L1 and L2, indicating the formation of the most stable ligand-HSA complex. Understanding the binding mechanisms of S-isoalkyl derivatives of the thiosalicylic acid to HSA may provide valuable data for the future studies of their biological activity and application as potential antitumor drugs.Communicated by Ramaswamy H. Sarma.
RESUMO
Inspired by the emergence of resistance to currently available antifungal therapy and by the great potential of metal complexes for the treatment of various diseases, we synthesized three new silver(I) complexes containing clinically used antifungal azoles as ligands, [Ag(ecz)2]SbF6 (1, ecz is econazole), {[Ag(vcz)2]SbF6}n (2, vcz is voriconazole), and [Ag(ctz)2]SbF6 (3, ctz is clotrimazole), and investigated their antimicrobial properties. The synthesized complexes were characterized by mass spectrometry, IR, UV-vis and 1H NMR spectroscopy, cyclic voltammetry, and single-crystal X-ray diffraction analysis. In the mononuclear complexes 1 and 3 with ecz and ctz, respectively, the silver(I) ion has the expected linear geometry, in which the azoles are monodentately coordinated to this metal center through the N3 imidazole nitrogen atom. In contrast, the vcz-containing complex 2 has a polymeric structure in the solid state in which the silver(I) ions are coordinated by four nitrogen atoms in a distorted tetrahedral geometry. DFT calculations were done to predict the most favorable structures of the studied complexes in DMSO solution. All the studied silver(I) complexes have shown excellent antifungal and good to moderate antibacterial activities with minimal inhibitory concentration (MIC) values in the ranges of 0.01-27.1 and 2.61-47.9 µM on the selected panel of fungi and bacteria, respectively. Importantly, the complexes 1-3 have exhibited a significantly improved antifungal activity compared to the free azoles, with the most pronounced effect observed in the case of complex 2 compared to the parent vcz against Candida glabrata with an increase of activity by five orders of magnitude. Moreover, the silver(I)-azole complexes 2 and 3 significantly inhibited the formation of C. albicans hyphae and biofilms at the subinhibitory concentration of 50% MIC. To investigate the impact of the complex 3 more thoroughly on Candida pathogenesis, its effect on the adherence of C. albicans to A549 cells (human adenocarcinoma alveolar basal epithelial cells), as an initial step of the invasion of host cells, was studied.
Assuntos
Complexos de Coordenação , Prata , Humanos , Prata/farmacologia , Prata/química , Candida , Antifúngicos/farmacologia , Antifúngicos/química , Azóis/farmacologia , Candida albicans , Testes de Sensibilidade Microbiana , Íons/farmacologia , Nitrogênio , Complexos de Coordenação/farmacologia , Complexos de Coordenação/químicaRESUMO
Organoruthenium pyrithione (1-hydroxypyridine-2-thione) complexes have been shown in our recent studies to be a promising family of compounds for development of new anticancer drugs. The complex [(η6-p-cymene)Ru(pyrithionato)(pta)]PF6 contains phosphine ligand pta (1,3,5-triaza-7-phosphaadamantane) as a functionality that improves the stability of the complex and its aqueous solubility. Here, we report our efforts to find pta alternatives and discover new structural elements to improve the biological properties of ruthenium anticancer drugs. The pta ligand was replaced by a selection of phosphine, phosphite, and arsine ligands to identify new functionalities, leading to improvement in inhibitory potency towards enzyme glutathione S-transferase. In addition, cytotoxicity in breast, bone, and colon cancers was investigated.
Assuntos
Antineoplásicos , Complexos de Coordenação , Compostos Organometálicos , Fosfinas , Rutênio , Rutênio/farmacologia , Rutênio/química , Compostos de Rutênio , Antineoplásicos/farmacologia , Antineoplásicos/química , Compostos Organometálicos/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Linhagem Celular TumoralRESUMO
Heavy metal ions can disrupt biological functions via multiple molecular mechanisms, including inhibition of enzymes. We investigate the interactions of human papain-like cysteine endopeptidases cathepsins L, K, and S with gallium and cerium ions, which are associated with medical applications. We compare these results with zinc and lead, which are known to inhibit thiol enzymes. We show that Ga3+, Ce3+, and Ce4+ ions inhibit all tested peptidases with inhibition constants in the low micromolar range (between 0.5 µM and 10 µM) which is comparable to Zn2+ ions, whereas inhibition constants of Pb2+ ions are one order of magnitude higher (30 µM to 150 µM). All tested ions are linear specific inhibitors of cathepsin L, but cathepsins K and S are inhibited by Ga3+, Ce3+, and Ce4+ ions via hyperbolic inhibition mechanisms. This indicates a mode of interaction different from that of Zn2+ and Pb2+ ions, which act as linear specific inhibitors of all peptidases. All ions also inhibit the degradation of insoluble elastin, which is a common target of these peptidases in various inflammatory diseases. Our results suggest that these ions and their compounds have the potential to be used as cysteine cathepsin inhibitors in vitro and possibly in vivo.
Assuntos
Cério , Gálio , Catepsina K/metabolismo , Catepsinas/metabolismo , Cisteína , Inibidores de Cisteína Proteinase/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Endopeptidases/metabolismo , Humanos , Íons , Cinética , ChumboRESUMO
In this study, we present the synthesis, kinetic studies of inhibitory activity toward aldo-keto reductase 1C (AKR1C) enzymes, and anticancer potential toward chemoresistant ovarian cancer of 10 organoruthenium compounds bearing diketonate (1-6) and hydroxyquinolinate (7-10) chelating ligands with the general formula [(η6-p-cymene)Ru(chel)(X)]n+ where chel represents the chelating ligand and X the chlorido or pta ligand. Our studies show that these compounds are potent inhibitors of the AKR enzymes with an uncommon inhibitory mechanism, where two inhibitor molecules bind to the enzyme in a first fast and reversible step and a second slower and irreversible step. The binding potency of each step is dependent on the chemical structure of the monodentate ligands in the metalloinhibitors with the chlorido complexes generally acting as reversible inhibitors and pta complexes as irreversible inhibitors. Our study also shows that compounds 1-9 have a moderate yet better anti-proliferative and anti-migration action on the chemoresistant ovarian cancer cell line COV362 compared to carboplatin and similar effects to cisplatin.
RESUMO
Four Pt(II) complexes of the general formula [Pt(L)(5,6-epoxy-1,10-phen)], where L is an anion of either malonic acid (mal, Pt1), 2-methylmalonic acid (Me-mal, Pt2), 2,2-dimethylmalonic acid (Me2-mal, Pt3) or 1,1-cyclobutanedicarboxylic acid (CBDCA, Pt4) and 5,6-epoxy-1,10-phen is 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, were synthesized and characterized by elemental microanalysis and different spectroscopic techniques. The crystal structure of anhydrous Pt3 complex was determined by single crystal X-ray diffraction. The in vitro anticancer activity of the platinum(II) complexes was investigated in human and murine cancer cell lines as well as in a normal murine cell line by MTT assay. The results show that the investigated platinum(II) complexes exhibit potent cytotoxic activity against murine breast carcinoma cells (4T1), human (HCT116) and murine (CT26) colorectal carcinoma cells. The Pt3 complex shows stronger selectivity against cancer cells compared to other platinum(II) complexes tested and thus exhibits beneficial antitumor activity, mainly by inducing apoptosis and inhibiting cell proliferation and migration. The Pt3 complex also exhibits significant in vivo antitumor activity in the orthotopical 4T1 tumor model without detected liver, kidney, lung, and heart toxicity. All the results indicate that these novel platinum(II) complexes have good antitumor activity on breast and colorectal cancer and have the potential to become possible candidates for cancer treatment.
Assuntos
Antineoplásicos , Complexos de Coordenação , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Malonatos/farmacologia , Camundongos , Platina/química , Platina/farmacologiaRESUMO
Drug resistance to existing anticancer agents is a growing clinical concern, with many first line treatments showing poor efficacy in treatment plans of some cancers. Resistance to platinum agents, such as cisplatin, is particularly prevalent in the treatment of ovarian cancer, one of the most common cancers amongst women in the developing world. Therefore, there is an urgent need to develop next generation of anticancer agents which can overcome resistance to existing therapies. We report a new series of organoruthenium(II) complexes bearing structurally modified pyrithione ligands with extended aromatic scaffold, which overcome platinum and adriamycin resistance in human ovarian cancer cells. The mechanism of action of such complexes appears to be unique from that of cisplatin, involving G1 cell cycle arrest without generation of cellular ROS, as is typically associated with similar ruthenium complexes. The complexes inhibit the enzyme thioredoxin reductase (TrxR) in a model system and reduce cell motility towards wound healing. Importantly, this work highlights further development in our understanding of the multi-targeting mechanism of action exhibited by transition metal complexes.
RESUMO
In this work, the various biological activities of eight organoruthenium(II) complexes were evaluated to reveal correlations with their stability and reactivity in aqueous media. Complexes with general formula [Ru(η6-p-cymene)(X,Y)(Z)] were prepared, where (X,Y) represents either an O,O-ligand (ß-diketone), N,O-ligand (8-hydroxyquinoline) or O,S-pyrithione-type ligands (pyrithione = 1-hydroxypyridine-2(1H)-thione) with Cl- or 1,3,5-triaza-7-phosphaadamantane (PTA) as a co-ligand (Z). The tested complexes inhibit the chlamydial growth on HeLa cells, and one of the complexes inhibits the growth of the human herpes simplex virus-2. The chlorido complexes with N,O- and O,S-ligands displayed strong antibacterial activity on Gram-positive strains including the resistant S. aureus (MRSA) and were cytotoxic in adenocarcinoma cell lines. Effect of the structural variation on the biological properties and solution stability was clearly revealed. The decreased bioactivity of the ß-diketone complexes can be related to their lower stability in solution. In contrast, the O,S-pyrithione-type complexes are highly stable in solution and the complexation prevents the oxidation of the O,S-ligands. Comparing the binding of PTA and the chlorido co-ligands, it can be concluded that PTA is generally more strongly coordinated to ruthenium, which at the same time decreased the reactivity of complexes with human serum albumin or 1-methylimidazole as well as diminished their bioactivity.
RESUMO
In addition to antibacterial and antitumor effects, synthetic ruthenium complexes have been reported to inhibit several medicinally important enzymes, including acetylcholinesterase (AChE). They may also interact with muscle-type nicotinic acetylcholine receptors (nAChRs) and thus affect the neuromuscular transmission and muscle function. In the present study, the effects of the organometallic ruthenium complex of 5-nitro-1,10-phenanthroline (nitrophen) were evaluated on these systems. The organoruthenium-nitrophen complex [(η6-p-cymene)Ru(nitrophen)Cl]Cl; C22H21Cl2N3O2Ru (C1-Cl) was synthesized, structurally characterized and evaluated in vitro for its inhibitory activity against electric eel acetylcholinesterase (eeAChE), human recombinant acetylcholinesterase (hrAChE), horse serum butyrylcholinesterase (hsBChE) and horse liver glutathione-S-transferase. The physiological effects of C1-Cl were then studied on isolated mouse phrenic nerve-hemidiaphragm muscle preparations, by means of single twitch measurements and electrophysiological recordings. The compound C1-Cl acted as a competitive inhibitor of eeAChE, hrAChE and hsBChE with concentrations producing 50 % inhibition (IC50) of enzyme activity ranging from 16 to 26 µM. Moreover, C1-Cl inhibited the nerve-evoked isometric muscle contraction (IC50 = 19.44 µM), without affecting the directly-evoked muscle single twitch up to 40 µM. The blocking effect of C1-Cl was rapid and almost completely reversed by neostigmine, a reversible cholinesterase inhibitor. The endplate potentials were also inhibited by C1-Cl in a concentration-dependent manner (IC50 = 7.6 µM) without any significant change in the resting membrane potential of muscle fibers up to 40 µM. Finally, C1-Cl (5-40 µM) decreased (i) the amplitude of miniature endplate potentials until a complete block by concentrations higher than 25 µM and (ii) their frequency at 10 µM or higher concentrations. The compound C1-Cl reversibly blocked the neuromuscular transmission in vitro by a non-depolarizing mechanism and mainly through an action on postsynaptic nAChRs. The compound C1-Cl may be therefore interesting for further preclinical testing as a new competitive neuromuscular blocking, and thus myorelaxant, drug.
Assuntos
Inibidores da Colinesterase/farmacologia , Contração Muscular/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Compostos de Rutênio/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/química , Electrophorus , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glutationa Transferase/antagonistas & inibidores , Cavalos , Humanos , Concentração Inibidora 50 , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Relaxamento Muscular/efeitos dos fármacos , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/química , Compostos de Rutênio/administração & dosagem , Compostos de Rutênio/químicaRESUMO
Ruthenium-arene complexes are a unique class of organometallic compounds that have been shown to have prominent therapeutic potencies. Here, we have investigated the interactions of Ru-cymene complexes with a zinc-finger protein NCp7, aiming to understand the effects of various ligands on the reaction. Five different binding modes were observed on selected Ru-complexes. Ru-cymene complex can bind to proteins through either noncovalent binding alone or through a combination of covalent and noncovalent binding modes. Moreover, the noncovalent interaction can promote the coordination of RuII to NCp7, resulting synergistic effects of the different ligands. The binding of Ru(Cym) complexes leads to dysfunction of NCp7 through zinc-ejection and structural perturbation. These results indicate that the reactivity of Ru-complexes can be modulated by ligands through different approaches, which could be closely correlated to their different therapeutic effects.
Assuntos
Rutênio/química , Dedos de Zinco/fisiologia , Antineoplásicos/química , Cimenos , Ligantes , MonoterpenosRESUMO
An organoruthenium(II) complex with pyrithione (2-mercaptopyridine N-oxide) 1 a has previously been identified by our group as a compound with promising anticancer potential without cytotoxicity towards non-cancerous cells. To expand the rather limited research on compounds of this type, an array of novel chlorido and 1,3,5-triaza-7-phosphaadamantane (pta) organoruthenium(II) complexes with methyl-substituted pyrithiones has been prepared. After thorough investigation of the aqueous stability of these complexes, their modes of action have been elucidated at the cellular level. Minor structural alterations in the ruthenium-pyrithionato compounds resulted in fine-tuning of their cytotoxicities. The best performing compounds, 1 b and 2 b, with a chlorido or pta ligand bound to ruthenium, respectively, and a methyl group at the 3-position of the pyrithione scaffold, have been further investigated. Both compounds trigger early apoptosis, induce the generation of reactive oxygen species and G1 arrest in A549 cancer cells, and show no strong interaction with DNA. However, only 1 b also inhibits thioredoxin reductase. Wound healing assays and mitochondrial function evaluation have revealed differences between these two compounds at the cellular level.
Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Piridinas/química , Rutênio/química , Tionas/química , Adamantano/análogos & derivados , Adamantano/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Compostos Organofosforados/química , Cicatrização/efeitos dos fármacosRESUMO
Lysosomal cysteine peptidase cathepsin B (catB) is an important tumor-promoting factor involved in tumor progression and metastasis representing a relevant target for the development of new antitumor agents. In the present study, we synthesized 11 ruthenium compounds bearing either the clinical agent nitroxoline that was previously identified as potent selective reversible inhibitor of catB activity or its derivatives. We demonstrated that organoruthenation is a viable strategy for obtaining highly effective and specific inhibitors of catB endo- and exopeptidase activity, as shown using enzyme kinetics and microscale thermophoresis. Furthermore, we showed that the novel metallodrugs by catB inhibition significantly impair processes of tumor progression in in vitro cell based functional assays at low noncytotoxic concentrations. Generally, by using metallodrugs we observed an improvement in catB inhibition, a reduction of extracellular matrix degradation and tumor cell invasion in comparison to free ligands, and a correlation with the reactivity of the monodentate halide leaving ligand.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Catepsina B/antagonistas & inibidores , Invasividade Neoplásica/prevenção & controle , Nitroquinolinas/farmacologia , Rutênio/farmacologia , Antineoplásicos/química , Neoplasias da Mama/patologia , Catepsina B/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Modelos Moleculares , Invasividade Neoplásica/patologia , Nitroquinolinas/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Rutênio/químicaRESUMO
The purpose of this work was to screen the antitumor actions of two metal organoruthenium-8-hydroxyquinolinato (Ru-hq) complexes to find a potential novel agent for bone, lung and breast chemotherapies. We showed that ruthenium compounds (1 and 2) impaired the cell viability of human bone (MG-63), lung (A549) and breast (MCF7) cancer cells with greater selectivity and specificity than cisplatin. Besides, complexes 1 and 2 decreased proliferation, migration and invasion on cell monolayers at lower concentrations (2.5-10 µM). In addition, both compounds induced genotoxicity revealed by the micronucleus test, which led to G2/M cell cycle arrest and induced the tumor cells to undergo apoptosis. On the other hand, in multicellular 3D models (multicellular spheroids; MCS), 1 and 2 overcame CDDP presenting lower IC50 values only in MCS of lung origin. Moreover, 1 outperformed 2 in MCS of bone and breast origin. Finally, our findings revealed that both compounds inhibited the cell invasion of multicellular spheroids, showing that complex 1 exhibited the most important antimetastatic action. Taken together, these results indicate that compound 1 is an interesting candidate to be tested on in vivo models as a novel strategy for anticancer therapy.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/metabolismo , Compostos Organometálicos/farmacologia , Oxiquinolina/farmacologia , Compostos de Rutênio/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Humanos , Modelos Biológicos , Compostos Organometálicos/química , Oxiquinolina/química , Rutênio/farmacologia , Compostos de Rutênio/químicaRESUMO
Two acetazolamide (AAZ) complexes with ruthenium(II) η6-p-cymene chloride were synthesised, characterised and tested for their inhibitory effects on several carbonic anhydrase (CA, EC 4.2.1.1) isoforms with pharmacological applications. Against human (h) isoform hCA I, the two complexes showed inhibition constants in the range of 8.5-23.4 nM (AAZ has a KI of 250 nM), against hCA II of 0.48-4.2 nM, whereas against hCA IX of 0.63-3.8 nM and against hCA XII of 0.04-0.52 nM, respectively. These highly effective ruthenium acetazolamide derivatives against the tumour-associated CA isoforms IX and XII warrant further in vivo studies, in hypoxic tumours overexpressing these enzymes.
Assuntos
Acetazolamida/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Acetazolamida/química , Antígenos de Neoplasias , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Rutênio/química , Relação Estrutura-AtividadeRESUMO
Thymoquinone (TQ), a natural compound with antimicrobial and antitumor activity, was used as the starting molecule for the preparation of 3-aminothymoquinone (ATQ) from which ten novel benzoxazole derivatives were prepared and characterized by elemental analysis, IR spectroscopy, mass spectrometry and NMR (¹H, 13C) spectroscopy in solution. The crystal structure of 4-methyl-2-phenyl-7-isopropyl-1,3-benzoxazole-5-ol (1a) has been determined by X-ray diffraction. All compounds were tested for their antibacterial, antifungal and antitumor activities. TQ and ATQ showed better antibacterial activity against tested Gram-positive and Gram-negative bacterial strains than benzoxazoles. ATQ had the most potent antifungal effect against Candida albicans, Saccharomyces cerevisiae and Aspergillus brasiliensis. Three benzoxazole derivatives and ATQ showed the highest antitumor activities. The most potent was 2-(4-fluorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1f). Western blot analyses have shown that this compound inhibited phosphorylation of protein kinase B (Akt) and Insulin-like Growth Factor-1 Receptor (IGF1R ß) in HeLa and HepG2 cells. The least toxic compound against normal fibroblast cells, which maintains similar antitumor activities as TQ, was 2-(4-chlorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1e). Docking studies indicated that 1e and 1f have significant effects against selected receptors playing important roles in tumour survival.
Assuntos
Benzoquinonas/química , Benzoxazóis , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Benzoquinonas/síntese química , Benzoxazóis/síntese química , Benzoxazóis/metabolismo , Células HeLa , Células Hep G2 , Humanos , Simulação de Acoplamento MolecularRESUMO
In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium-8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halogen atoms in different positions which enables to study effect of the substituents on physico-chemical and biological properties. The determined crystal structures of novel complexes expectedly show the cymene ring, a bidentately coordinated deprotonated hq and a halide ligand (chlorido or iodido) coordinated to the ruthenium central ion. In previous studies the anticancer potential of organoruthenium complex with 8-hydroxyquinoline ligand clioquinol was well established and we have decided to perform an extended biological evaluation (antibacterial and antitumor activity) of the whole series of halo-substituted analogs. Beside the cytotoxic potential of studied compounds also the effect of two selected complexes (9 and 10) on apoptosis induction in MG-63 and A549 cells was also studied via externalization of phosphatidylserine at the outer plasma membrane leaflet. Both selected complexes that gave best preliminary cytotoxicity results contain bromo substituted hq ligands. Apoptosis induction results are in agreement with the cell viability assays suggesting the higher and more selective anticancer activity of complex 10 in comparison to complex 9 on MG-63 cells.
Assuntos
Antibacterianos , Antineoplásicos , Apoptose/efeitos dos fármacos , Neoplasias , Compostos Organometálicos , Oxiquinolina , Rutênio , Células A549 , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Oxiquinolina/química , Oxiquinolina/farmacologia , Rutênio/química , Rutênio/farmacologiaRESUMO
Over the past few years, the organometalled compounds, including ruthenium, gained a lot of attention as anticancer agents. We report on the clioquinol-ruthenium complex [Ru(η6-p-cymene)(Cq)Cl] as a potent inhibitor of cathepsin B, a lysosomal cysteine peptidase, involved in tumour cell invasion and metastasis. In the low micromolar concentration range, the clioquinol-ruthenium complex did not exhibit cytotoxic effects on MCF-10A neoT and U-87 MG cells; it did, however, significantly reduce their ability for extracellular matrix degradation and invasiveness in two independent cell-based models, measuring either electrical impedance in real time or the growth of multicellular tumour spheroids implanted in Matrigel, a model representing the extracellular matrix. These results establish ruthenium based organometallic compounds as promising candidates for further pre-clinical studies as anticancer therapeutics.
Assuntos
Antineoplásicos/farmacologia , Catepsina B/antagonistas & inibidores , Clioquinol/farmacologia , Inibidores Enzimáticos/farmacologia , Invasividade Neoplásica/prevenção & controle , Neoplasias/tratamento farmacológico , Rutênio/farmacologia , Antineoplásicos/química , Catepsina B/metabolismo , Linhagem Celular Tumoral , Clioquinol/análogos & derivados , Cimenos , Inibidores Enzimáticos/química , Humanos , Monoterpenos/química , Monoterpenos/farmacologia , Invasividade Neoplásica/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Rutênio/químicaRESUMO
Four ruthenium complexes of clinically used zinc ionophore pyrithione and its oxygen analog 2-hydroxypyridine N-oxide were prepared and evaluated as inhibitors of enzymes of the aldo-keto reductase subfamily 1C (AKR1C). A kinetic study assisted with docking simulations showed a mixed type of inhibition consisting of a fast reversible and a slow irreversible step in the case of both organometallic compounds 1A and 1B. Both compounds also showed a remarkable selectivity towards AKR1C1 and AKR1C3 which are targets for breast cancer drug design. The organoruthenium complex of ligand pyrithione as well as pyrithione itself also displayed toxicity on the hormone-dependent MCF-7 breast cancer cell line with EC50 values in the low micromolar range.
Assuntos
Aldo-Ceto Redutases/antagonistas & inibidores , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Piridinas/farmacologia , Rutênio/farmacologia , Tionas/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Humanos , Células MCF-7 , Piridinas/química , Rutênio/química , Tionas/químicaRESUMO
Three novel complexes have been prepared through reactions of precursor [(dmso)2H][trans-RuCl4(dmso-S)2] (P) and 1,10-phenanthroline (phen) at different conditions. Whereas the analogs of mer-[RuCl3(dmso-S)(phen)] (1) and [Ru(phen)3]Cl2·6CH3OH (3·6CH3OH) have already been prepared by other synthetic routes before, product (H3O)[RuCl4(phen)]·4H2O (2·4H2O) is unprecedented. In the latter, isolated from highly acidic medium, one strongly bound dmso molecule in precursor P was substituted by chloride. Biological activity of 1 and previously isolated ruthenium-purine complexes ([mer-RuCl3(dmso-S)(acv)(CH3OH)] (4) (acv = acyclovir); [trans-RuCl4(dmso-S)(guaH)] (5) (guaH = protonated guanine)) was tested and compared. These data show that compounds 1, 4 and 5 are slightly cytotoxic against B-16 malignant melanoma cells but not against non-transformed V-79-379A cells. It seems that coordinated phen ligand increases the cytotoxicity of 1 in comparison to ruthenium precursor. The inability of tested compounds to induce lysis of bovine erythrocytes suggests that their cytotoxic effect is not due to the membrane damage.