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1.
J Med Chem ; 67(8): 6081-6098, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38401050

RESUMEN

In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane (PPh3) or 1,2-bis(diphenylphosphino)ethane (dppe) ligands. All compounds were characterized by diverse analytical methods including ESI-MS spectrometry; NMR, UV-vis, and FTIR spectroscopies; and elemental analysis. Moreover, several compounds were also studied by X-ray single-crystal diffraction. Subsequently, the compounds were investigated for their anticancer activity against drug-resistant and -sensitive cancer cells. Noteworthily, neither carboplatin and oxaliplatin resistance nor p53 deletion impacted on their anticancer efficacy. MES-OV cells displayed exceptional hypersensitivity to the dppe-containing drugs. This effect was not based on thioredoxin reductase inhibition, enhanced drug uptake, or apoptosis induction. In contrast, dppe silver drugs induced paraptosis, a novel recently described form of programmed cell death. Together with the good tumor specificity of this compound's class, this work suggests that dppe-containing silver complexes could be interesting drug candidates for the treatment of resistant ovarian cancer.


Asunto(s)
2,2'-Dipiridil , Antineoplásicos , Fosfinas , Plata , Humanos , Fosfinas/química , Fosfinas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Plata/química , Plata/farmacología , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacología , Línea Celular Tumoral , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Apoptosis/efectos de los fármacos , Cristalografía por Rayos X , Ligandos , Muerte Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Resistencia a Antineoplásicos/efectos de los fármacos
2.
Eur J Med Chem ; 262: 115922, 2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-37944388

RESUMEN

A family of ten novel ruthenium(II)-cyclopentadienyl organometallics of general formula [Ru(η5-C5H5)(N,N)(PPh2(C6H4COOR)][CF3SO3] (1-10) in which (N,N) = 4,4'-R'-2,2'-bipyridyl (R = -H or -CH2CH2OH; R' = -H, -CH3, -OCH3, -CH2OH, and -CH2-biotin) was prepared from [Ru(η5-C5H5)(PPh2(C6H4COOH))2Cl]. All compounds were fully characterized by means of several spectroscopic and analytical techniques, and the molecular structures of [Ru(η5-C5H5)(PPh2(C6H4COOH))2Cl], 1, 3 and 4 have been additionally studied by single-crystal X-ray diffraction. The anticancer activity of all compounds was evaluated in sensitive and multidrug-resistant counterpart cell lines from human colorectal cancer (Colo 205 and Colo 320) and non-small cell lung cancer NSCLC (A549, NCI-H460 versus NCI-H460/R) as well. Notably, compounds 6 and 7 (R CH2CH2OH and (N,N) = bipy or Me2bipy, respectively) showed antiproliferative effect against both cell lines with high intrinsic selectivity towards cancer cells. The antibacterial activity of all compounds was also evaluated against both Gram negative and Gram positive strains, and some compounds in the series showed potent antibacterial activity against Staphylococcus aureus strains, including the methicillin-resistant MRSA strains. Solution speciation studies revealed that the complexes bearing the PPh2(C6H4COO-) ligand are neutral at physiological pH (7.4) in contrast with their ethylene glycol derivatives that have a permanent positive charge. While all compounds are lipophilic, the difference in the distribution coefficient for neutral and charged complexes is around one order of magnitude. Complexes 6 and 7 exhibited excellent biological activity and were selected for further studies. Spectrofluorometric methods were used to investigate their interaction with biomolecules such as human serum albumin (HSA) and calf thymus DNA (ct-DNA). For these complexes, binding site II of HSA is a possible binding pocket through non-covalent interactions. The release of ethidium from the DNA adduct by the charged complexes proves their interaction with DNA in contrast to the neutral ones. In conclusion, Ru(II)-cyclopentadienyl complexes with 2,2'-bipyridyl-derivatives and an ethylene glycol moiety tethered to the phenylphosphane co-ligand are very promising from a therapeutic perspective, in particular complexes 6 and 7 that display remarkable antibacterial activity with a high anti-proliferative effect against colon and non-small cell lung cancers, both clinically challenging neoplasias in need of effective solutions.


Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Complejos de Coordinación , Neoplasias Pulmonares , Rutenio , Humanos , 2,2'-Dipiridil , Ligandos , Albúmina Sérica Humana , ADN/química , Antibacterianos/farmacología , Antibacterianos/química , Glicoles de Etileno , Antineoplásicos/farmacología , Antineoplásicos/química , Rutenio/farmacología , Rutenio/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Línea Celular Tumoral
3.
Bioinorg Chem Appl ; 2023: 6669394, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37808953

RESUMEN

Piano-stool-{CpRu} complexes containing 1,3,5-triaza-7-phosphaadamantane (PTA), N-methyl-1,3,5-triaza-7-phosphaadamantane (mPTA), and 3,7-dimethyl-1,3,7-triaza-5-phosphabyciclo[3.3.1]nonane (dmoPTA) were evaluated as drugs against breast cancer. The evaluated compounds include two new examples of this family, the complexes [RuCp(DMSO-κS)(HdmoPTA)(PPh3)](CF3SO3)2 (8) and [RuCp(PPh3)2-µ-dmoPTA-1κP-2κ2N,N'-PdCl2](CF3SO3) (11), which have been synthesized and characterized by NMR, IR, and single-crystal X-ray diffraction. The cytotoxic activity of compounds was evaluated against MDA-MB-231 breast cancer cells, and the three most active complexes were further tested against the hormone-dependent MCF-7 breast cancer cell line. Their cell death mechanism and ruthenium uptake were also evaluated, as well as their binding ability to human serum albumin.

4.
J Med Chem ; 66(20): 14080-14094, 2023 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-37616241

RESUMEN

The search for more effective and selective drugs to overcome cancer multidrug resistance is urgent. As such, a new series of ruthenium-cyclopentadienyl ("RuCp") compounds with the general formula [Ru(η5-C5H4R)(4,4'-R'-2,2'-bipy)(PPh3)] were prepared and fully characterized. All compounds were evaluated toward non-small cell lung cancer cells with different degrees of cisplatin sensitivity (A549, NCI-H2228, Calu-3, and NCI-H1975), showing better cytotoxicity than the first-line chemotherapeutic drug cisplatin. Compounds 2 and 3 (R' = -OCH3; R = CHO (2) or CH2OH (3)) further inhibited the activity of P-gp and MRP1 efflux pumps by impairing their catalytic activity. Molecular docking calculations identified the R-site P-gp pocket as the preferred one, which was further validated using site-directed mutagenesis experiments in P-gp. Altogether, our results unveil the first direct evidence of the interaction between P-gp and "RuCp" compounds in the modulation of P-gp activity and establish them as valuable candidates to circumvent cancer MDR.


Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Rutenio , Humanos , Antineoplásicos/farmacología , Rutenio/farmacología , Cisplatino/farmacología , Simulación del Acoplamiento Molecular , Compuestos de Rutenio/farmacología , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos
5.
J Inorg Biochem ; 238: 112058, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36375357

RESUMEN

With the aim to incorporate pharmacophore motifs into the Ru(II)-polypyridyl framework, compounds [Ru(II)(1,10-phenantroline)2(2-(2-pyridyl)benzo[b]thiophene)](CF3SO3)2 (1) and [Ru(II)(1,10-phenantroline)2(2-(2-pyridyl)benzimidazole)](CF3SO3)2 (2) were prepared, characterized and tested for their antitumor potential. The solid-state structure of the compounds was confirmed by single-crystal X-ray diffraction analysis. The solution behavior of both complexes was investigated, namely their solubility, stability, and lipophilicity in physiological mimetic conditions, as well as an eventual uptake by passive diffusion. In vitro anticancer activity of the complexes on ovarian and different colon cancer cells and apoptosis induction by the complexes were studied. A slow transformation process was observed for complex 1 in aqueous solution when exposed to sunlight, while complex 2 undergoes deprotonation (pKa = 7.59). The lipophilicity of this latter complex depends strongly on the pH and ionic strength. In contrast, 1 is rather hydrophilic under various conditions. Complex 1 was highly cytotoxic on Colo-205 human colon (IC50 = 7.87 µM) and A2780 ovarian (IC50 = 2.2 µM) adenocarcinoma cell lines, while 2 displayed moderate anticancer activity (30.9 µM and 18.0 µM, respectively). The complexes induced late apoptosis and necrosis. Only a weak binding of the complexes to human serum albumin, the main transport protein in blood serum, was found. However, a more significant binding to calf thymus DNA was observed in UV-visible titrations and fluorometric dye displacement studies. Detailed analysis of fluorescence lifetime data collected for the latter systems reveals not only the partial intercalation of the complexes, but goes beyond the usual simplified interpretations.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Neoplasias Ováricas , Rutenio , Humanos , Femenino , Rutenio/química , Línea Celular Tumoral , Tiofenos , Antineoplásicos/química , Bencimidazoles/farmacología , Complejos de Coordinación/química
6.
J Inorg Biochem ; 236: 111961, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36049258

RESUMEN

Due to the growing prevalence of cancer diseases, new therapeutic options are urgently needed, and drugs based on metal ions other than platinum are alternatives with exciting possibilities. We report the synthesis, characterization and biological effect of mixed-ligand Fe(III)-aminophenolate complexes derived from salicylaldehyde and L-tryptophan with quinoline derivatives as co-ligands, namely 8-hydroxyquinoline (8HQ), [Fe(L)(8HQ)(H2O)] (1) and its 5-cloro derivative (Cl8HQ), [Fe(L)(Cl8HQ)(H2O)] (2). The complex bearing the aminophenolate and lacking the quinoline co-ligand, [Fe(L)(Cl)(H2O)2] (3), was prepared for comparison. The analytical and spectroscopic characterization revealed that 1 and 2 are octahedral Fe(III) complexes with the aminophenolate acting as a dianionic tridentate ligand and 8HQ co-ligands as bidentate chelates. Spectroscopic techniques and molecular docking studies were used to evaluate the ability of these complexes to bind bovine serum albumin (BSA) and calf thymus DNA. Complex 2 [Fe(L)(Cl8HQ)(H2O)] was the one showing higher affinity for both biomolecules. Cell viability was assessed in breast, colorectal and bone human cancer cell lines. 1 and 2 were found to be more active than cisplatin in all cell lines tested. A non-tumoral fibroblast line (L929, mouse non-tumoral fibroblasts) was used to evaluate selectivity. The results evidence that 2 shows much higher selectivity than 1 in all cell lines tested, but particularly in bone cancer cells in which selectivity index (SI) values are 8.0 and 18.8 for 1 and 2, respectively.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Cisplatino , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Compuestos Férricos , Humanos , Ligandos , Ratones , Simulación del Acoplamiento Molecular , Oxiquinolina/farmacología , Platino (Metal) , Bases de Schiff/química , Bases de Schiff/farmacología , Albúmina Sérica Bovina/metabolismo , Triptófano
7.
Int J Pharm ; 623: 121925, 2022 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-35718249

RESUMEN

Malignant melanoma is an aggressive and deadly form of skin cancer and novel and improved therapeutic options are needed. A promising strategy involves the use of metallodrugs combined with liposomes for targeted delivery to cancer cells. In this work, a family of iron(III) complexes was synthesized bearing a trianionic aminobisphenolate ligand (L) and phenanthroline-type co-ligands (NN). Four ternary iron complexes of general formula [Fe(L)(NN)] were obtained: [Fe(L)(amphen)] (1), [Fe(L)(phen)] (2), [Fe(L)(Clphen)] (3), and [Fe(L)(Mephen)] (4), as well as a fifth complex [Fe(L)(NEt3)(H2O)] (5) without the bidentate co-ligand. All complexes were characterized by analytic and spectroscopic techniques and demonstrated to be stable in aqueous environment. Complexes 1 and 2 were able to bind DNA and presented high cytotoxic activity towards human cancer cells. Complex 1 (IronC) was selected for incorporation into different liposomal formulations, which were fully characterized and screened against murine melanoma cells. The IronC liposomal formulation with the highest incorporation efficiency (∼95%) and a low IC50 value (7.1 ± 0.7 µM) was selected for in vivo evaluation. In a syngeneic murine melanoma model the liposomal formulation of IronC yielded the highest impairment on tumour progression when compared with the control, temozolomide, and with the iron complex in free form.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Melanoma , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Complejos de Coordinación/química , Humanos , Hierro/química , Ligandos , Liposomas , Melanoma/tratamiento farmacológico , Ratones , Fenantrolinas/química , Fenantrolinas/metabolismo , Fenantrolinas/farmacología
8.
Front Mol Biosci ; 9: 1059116, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36660430

RESUMEN

This work addresses the possible role of the cell membrane in the molecular mechanism of action of two salan-type ruthenium complexes that were previously shown to be active against human tumor cells, namely [Ru(III)(L1)(PPh3)Cl] and [Ru(III)(L2)(PPh3)Cl] (where L1 is 6,6'-(1R,2R)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(3-methoxyphenol); and L2 is 2,2'-(1R,2R)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(4-methoxyphenol)). One-component membrane models were first used, a disordered fluid bilayer of dioleoylphosphatodylcholine (DOPC), and an ordered rigid gel bilayer of dipalmitoylphosphatidylcholine. In addition, two quaternary mixtures of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin and cholesterol were used to mimic the lipid composition either of mammalian plasma membrane (1:1:1:1 mol ratio) or of a cancer cell line membrane (36.2:23.6:6.8:33.4 mol ratio). The results show that both salan ligands L1 and L2 bind relatively strongly to DOPC bilayers, but without significantly affecting their structure. The ruthenium complexes have moderate affinity for DOPC. However, their impact on the membranes was notable, leading to a significant increase in the permeability of the lipid vesicles. None of the compounds compromised liposome integrity, as revealed by dynamic light scattering. Fluorescence spectroscopy studies revealed changes in the biophysical properties of all membrane models analyzed in the presence of the two complexes, which promoted an increased fluidity and water penetration into the lipid bilayer in the one-component systems. In the quaternary mixtures, one of the complexes had an analogous effect (increasing water penetration), whereas the other complex reorganized the liquid ordered and liquid disordered domains. Thus, small structural differences in the metal ligands may lead to different outcomes. To better understand the effect of these complexes in cancer cells, the membrane dipole potential was also measured. For both Ru complexes, an increase in the dipole potential was observed for the cancer cell membrane model, while no alteration was detected on the non-cancer plasma membrane model. Our results show that the action of the Ru(III) complexes tested involves changes in the biophysical properties of the plasma membrane, and that it also depends on membrane lipid composition, which is frequently altered in cancer cells when compared to their normal counterparts.

9.
Inorg Chem ; 60(5): 2914-2930, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33570919

RESUMEN

Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl][CF3SO3] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC50 values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC50 value about 1 order of magnitude higher than any IC50 concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy.


Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Fosfinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/metabolismo , Complejos de Coordinación/toxicidad , ADN/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Fibroblastos/efectos de los fármacos , Humanos , Fosfinas/síntesis química , Fosfinas/metabolismo , Fosfinas/toxicidad , Unión Proteica , Especies Reactivas de Oxígeno/metabolismo , Rutenio/química , Albúmina Sérica Humana/metabolismo , Pez Cebra
10.
Data Brief ; 27: 104548, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31681825

RESUMEN

This dataset is related to the research article entitled "May iron(III) complexes containing phenanthroline derivatives as ligands be prospective anticancer agents?" [1]. It includes the characterization by UV-Vis absorption spectroscopy and magnetic techniques of a group of mixed ligand Fe(III) complexes bearing a tripodal aminophenolate ligand L2-, H2L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl)amine, and different aromatic bases (NN = 2,2'-bipyridine [Fe(L)(bipy)]PF6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO3 (3), [Fe(L)(amphen)]PF6 (3a), [Fe(L)(Clphen)]PF6 (4), [Fe(L)(epoxyphen)]PF6 (5) (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline), as well as [Fe(L)(EtOH)]NO3 (6), [Fe(phen)Cl3] (7) and [Fe(amphen)Cl3] (8). Data on their hydrolytic stability in physiological buffers is shown, as well as on their interaction with calf thymus DNA by spectroscopic tools. Additionally, the anticancer efficacy and the cellular death mechanisms activated in response to these drugs in HeLa, H1299 and MDA-MB-231 cells are provided.

11.
Molecules ; 24(16)2019 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-31394747

RESUMEN

The steady rise in the cancer burden and grim statistics set a vital need for new therapeutic solutions. Given their high efficiency, metallodrugs are quite appealing in cancer chemotherapy. This work examined the anticancer activity of an anti-trypanosomal ruthenium-based compound bearing the 5-nitrofuryl pharmacophore, [RuII(dmso)2(5-nitro-2-furaldehyde semicarbazone)] (abbreviated as RuNTF; dmso is the dimethyl sulfoxide ligand). The cytotoxicity of RuNTF was evaluated in vitro against ovarian adenocarcinoma, hormone-dependent breast adenocarcinoma, prostate carcinoma (grade IV) and V79 lung fibroblasts human cells. The activity of RuNTF was similar to the benchmark metallodrug cisplatin for the breast line and inactive against the prostate line and lung fibroblasts. Given the known role of serum protein binding in drug bioavailability and the distribution via blood plasma, this study assessed the interaction of RuNTF with human serum albumin (HSA) by circular dichroism (CD) and fluorescence spectroscopy. The fluorescence emission quenching from the HSA-Trp214 residue and the lifetime data upon RuNTF binding evidenced the formation of a 1:1 {RuNTF-albumin} adduct with log Ksv = (4.58 ± 0.01) and log KB = (4.55 ± 0.01). This is supported by CD data with an induced CD broad band observed at ~450 nm even after short incubation times. Importantly, the binding to either HSA or human apo-transferrin is beneficial to the cytotoxicity of the complex towards human cancer cells by enhancing the cytotoxic activity of RuNTF.


Asunto(s)
Proteínas Sanguíneas/química , Complejos de Coordinación/química , Rutenio/química , Semicarbazonas/química , Algoritmos , Antineoplásicos/química , Antineoplásicos/farmacología , Proteínas Sanguíneas/metabolismo , Dicroismo Circular , Interacciones Farmacológicas , Humanos , Modelos Moleculares , Modelos Teóricos , Estructura Molecular , Unión Proteica , Rutenio/metabolismo , Albúmina Sérica Humana/química , Albúmina Sérica Humana/metabolismo
12.
Dalton Trans ; 48(24): 8702-8716, 2019 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-31123737

RESUMEN

In the quest for therapeutic iron-based metallodrugs, two new mixed-ligand iron(iii) complexes bearing the tripodal aminobisphenolate ligand N,N-bis(3,5-dimethyl-2-hydroxybenzyl)-N-(2-pyridylmethyl)amine (H2L) and hydroxyquinoline co-ligands, 8-hydroxyquinoline (8HQ) or 5-chloro-8-hydroxyquinoline (Cl8HQ), are synthesized, fully characterized and formulated as [Fe(L)(8HQ)] (1) and [Fe(L)(Cl8HQ)] (2), respectively. These high-spin Fe(iii) complexes are stable in aqueous solution in the presence of equimolar amounts of Bovine Serum Albumin (BSA), which indicates a likely binding interaction with the protein. In fact, binding constant log values at pH 7.4 for HSA of 5.08 and 6.35 were obtained for 1 and 2, respectively. Compounds 1 and 2 are cytotoxic against both human triple-negative breast adenocarcinoma (MDA-MB-231) and human cervical carcinoma (HeLa) cancer cells, and the activity is significantly improved by inclusion of the co-ligands 8HQ and Cl8HQ to the precursor complex Fe(L). Moreover, 1 and 2 are more active than 8HQ and Cl8HQ, particularly at lower incubation times tested, 24 and 48 h. Cells treated with the complexes display typical features of apoptosis as assessed by cellular morphology, DNA condensation and TUNEL analysis. COMET assays show that both drug candidates induce genomic damage in both cell lines. The complexes exhibit DNA cleavage activity and DNA damage that may be related to their ability to generate ROS. Overall, data supports that 1 and 2 are both active anticancer drug candidates within the low micromolar range. This is particularly interesting in the case of the breast MDA-MB-231 line, a model for triple-negative breast cancer that is an aggressive form of breast cancer, highly invasive and with limited treatment options and very poor prognosis. Furthermore, both complexes exhibited good anti-Mycobacterium tuberculosis activity, suggesting that 1 and 2 might have a wide spectrum of biological activity and justify further research.


Asunto(s)
Hidroxiquinolinas/química , Hierro/química , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bovinos , Línea Celular Tumoral , Humanos , Mycobacterium tuberculosis/efectos de los fármacos , Compuestos Organometálicos/metabolismo , Albúmina Sérica Bovina/metabolismo
13.
Eur J Med Chem ; 176: 492-512, 2019 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-31132480

RESUMEN

We report the design, synthesis and biological studies on a group of mixed ligand Fe(III) complexes as anti-cancer drug candidates, namely their interaction with DNA, cytotoxicity and mechanism(s) of action. The aim is to obtain stable, efficient and selective Fe-complexes to be used as anti-cancer agents with less damaging side effects than previously reported compounds. Five ternary Fe(III) complexes bearing a tripodal aminophenolate ligand L2-, H2L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl)amine, and different aromatic bases NN = 2,2'-bipyridine [Fe(L)(bipy)]PF6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO3 (3), [Fe(L)(amphen)]PF6 (3a), [Fe(L)(Clphen)]PF6 (4), [Fe(L)(epoxyphen)]PF6 (5) (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline) and the [Fe(L)(EtOH)]NO3 (6) complex are synthesized. The compounds are characterized in the solid state and in solution by elemental analysis, ESI-MS, magnetic susceptibility measurements and FTIR, UV-Vis, 1H and 13C NMR and fluorescence spectroscopies. [Fe(phen)Cl3] and [Fe(amphen)Cl3] were also prepared for comparison purposes. Spectroscopic binding studies indicate groove binding as the main interaction for most complexes with DNA, and for those containing amphen a B- to Z-DNA conformational change is proposed to occur. As determined via MTT analysis all compounds 1-6 are cytotoxic against a panel of three different cell lines (HeLa, H1299, MDA-MB-231). For selected compounds with promising cytotoxic activity, apoptosis was evaluated using cell and DNA morphology, TUNEL, Annexin V/7AAD staining and caspase3/7 activity. The compounds induce oxidative DNA damage on plasmid DNA and in cell culture as assessed by 8-oxo-Guanine and γH2AX staining. Comet assay confirmed the presence of genomic damage. There is also increased reactive oxygen species formation following drug treatment, which may be the relevant mechanism of action, thus differing from that normally assumed for cisplatin. The Fe(III)-complexes were also tested against strains of M. Tuberculosis (MTb), complex 2 depicting higher anti-MTb activity than several known second line drugs. Hence, these initial studies show prospective anti-cancer and anti-MTb activity granting promise for further studies.


Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Hierro/química , Fenantrolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , Antituberculosos/síntesis química , Antituberculosos/química , Antituberculosos/farmacología , Antituberculosos/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/toxicidad , ADN/química , Roturas del ADN de Doble Cadena/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Diseño de Fármacos , Estabilidad de Medicamentos , Humanos , Ligandos , Mycobacterium tuberculosis/efectos de los fármacos , Fenantrolinas/síntesis química , Fenantrolinas/química , Fenantrolinas/toxicidad , Estudios Prospectivos , Especies Reactivas de Oxígeno/metabolismo
14.
Inorg Chem ; 57(21): 13150-13166, 2018 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-30339386

RESUMEN

Ruthenium(II) complexes are currently considered a viable alternative to the widely used platinum complexes as efficient anticancer agents. We herein present the synthesis and characterization of half-sandwich ruthenium compounds with the general formula [Ru( p-cymene)(L-N,N)Cl][CF3SO3] (L = 3,6-di-2-pyridyl-1,2,4,5-tetrazine (1) 6,7-dimethyl-2,3-bis(pyridin-2-yl)quinoxaline (2)), which have been synthesized by substitution reactions from the precursor dimer [Ru( p-cymene)(Cl)(µ-Cl)]2 and were characterized by elemental analysis, mass spectrometry, 1H NMR, UV-vis, and IR spectroscopy, conductivity measurements, and cyclic voltammetry. The molecular structure for complex 2 was determined by single-crystal X-ray diffraction. The cytotoxic activity of these compounds was evaluated against human tumor cells, namely ovarian carcinoma A2780 and breast MCF7 and MDAMB231 adenocarcinoma cells, and against normal primary fibroblasts. Whereas the cytotoxic activity of 1 is moderate, IC50 values found for 2 are among the lowest previously reported for Ru( p-cymene) complexes. Both compounds present no cytotoxic effect in normal human primary fibroblasts when they are used at the IC50 concentration in A2780 and MCF7 cancer cells. Their antiproliferative capacity is associated with a combined mechanism of apoptosis and autophagy. A strong interaction with DNA was observed for both with a binding constant value of the same magnitude as that of the classical intercalator [Ru(phen)2(dppz)]2+. Both complexes bind to human serum albumin with moderate to strong affinity, with conditional binding constants (log Kb) of 4.88 for complex 2 and 5.18 for complex 1 in 2% DMSO/10 mM Hepes pH7.0 medium. The acute toxicity was evaluated in zebrafish embryo model using the fish embryo acute toxicity test (FET). Remarkably, our results show that compounds 1 and 2 are not toxic/lethal even at extremely high concentrations. The novel compounds reported herein are highly relevant antitumor metallodrug candidates, given their in vitro cytotoxicity toward cancer cells and the lack of in vivo toxicity.


Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Monoterpenos/farmacología , Rutenio/farmacología , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/efectos adversos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cimenos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Monoterpenos/efectos adversos , Monoterpenos/química , Rutenio/efectos adversos , Rutenio/química , Relación Estructura-Actividad , Pez Cebra
15.
J Inorg Biochem ; 168: 27-37, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28006663

RESUMEN

Two recently published Ru(III) complexes bearing (N2O2) tetradentate bis(aminophenolate) ligands, formulated as [Ru(III)(salan)(PPh3)Cl] (salan is the tetradentate ligand 6,6'-(1S,2S)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(3-methoxyphenol) in complex 1, or 2,2'-(1S,2S)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(4-methoxyphenol) in complex 2; PPh3 is triphenylphosphane) and found very active against ovarian and breast adenocarcinoma human cells were studied to outline their antitumor mode of action. The human cisplatin-sensitive ovarian adenocarcinoma line A2780 was used herein as the cell model. At a 24h challenge (similarly as found before for 72h) both complexes are active, their cytotoxicity being comparable to that of cisplatin in the same conditions. As a possible target in the cell for their action, the interaction of 1 and 2 with DNA was assessed through displacement of well-established DNA fluorescent probes (ethidium bromide, EB, and 4',6-diamidino-2-phenylindole, DAPI) through steady-state and time-resolved fluorescence spectroscopy. The whole emission spectra were analyzed globally for the binary DNA-probe and ternary DNA-probe-Ru(III) complex systems. Both Ru(III) complexes can displace EB and bind to DNA with similar and moderate strong affinity with conditional stability constants of logK'=(5.05±0.01) for 1 and logK'=(4.79±0.01) for 2. The analysis of time-domain fluorescence intensity decays confirmed both qualitatively and quantitatively the model used to describe the binding and competition processes. Cell studies indicated that apoptosis is the major mechanism of cell death for both complexes, with 2 (the more active complex) promoting that process more efficiently than 1. Transmission electron micrographs revealed clear alterations on intracellular organization consistent with the induction of programmed cell death processes.


Asunto(s)
Aminofenoles/química , Apoptosis/efectos de los fármacos , Complejos de Coordinación/farmacología , Rutenio/farmacología , Aminofenoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , ADN/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Microscopía Electrónica de Transmisión , Modelos Moleculares , Rutenio/química
16.
Anticancer Agents Med Chem ; 17(1): 126-136, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27671310

RESUMEN

BACKGROUND: Ruthenium-based anti-cancer compounds are proposed as viable alternatives that might circumvent the disadvantages of platinum-based drugs, the only metallodrugs in clinical use for chemotherapy. Organometallic complexes in particular hold great potential as alternative therapeutic agents since their cytotoxicity involves different modes of action and present reduced toxicity profiles. OBJECTIVE: During the last few years our research group has been reporting on a series of organometallic ruthenium(II)- cyclopentadienyl complexes with important cytotoxicity against several cancer cell lines, surpassing cisplatin in activity. We report herein preliminary in vivo studies with one representative compound of this family, with exceptional activity against several human cancer cell lines, including the glycolytic and highly metastatic MDAMB231 cell line used in this study. METHOD: The anti-tumor activity of our compound was studied in vivo on N:NIH(S)II-nu/nu nude female mice bearing triple negative breast cancer (TNBC) orthotopic tumors. Administration of 2.5 mg/kg/day during ten days caused cell death mostly by necrosis (in vitro and in vivo), inducing tumor growth suppression of about 50% in treated animals when compared to controls. RESULTS: The most remarkable result supporting the effectiveness and potential of this drug was the absence of metastases in the main organs of treated animals, while metastases were present in the lungs of all control mice, as revealed by histopathological and immunohistochemical analysis. CONCLUSION: These in vivo studies suggest a dual effect for our drug not only by suppressing growth at the primary tumor tissue but also by inhibiting its metastatic behavior. Altogether, these results represent a benchmark and a solid starting point for future studies.


Asunto(s)
Antineoplásicos/uso terapéutico , Mama/efectos de los fármacos , Compuestos Organometálicos/uso terapéutico , Rutenio/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos/química , Mama/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Desnudos , Compuestos Organometálicos/química , Rutenio/química , Neoplasias de la Mama Triple Negativas/patología
17.
Future Med Chem ; 8(5): 527-44, 2016 04.
Artículo en Inglés | MEDLINE | ID: mdl-27096164

RESUMEN

Research on the field of metal complexes for the treatment of cancer diseases has attracted increasing interest due to the urgency in finding more efficient and selective treatments. Owing to their wide structural diversity, organometallic complexes appear as potential alternatives to the design of new anticancer candidates. Herein, we review recent progress in our work toward the development of new drugs based on Ru(II)- and Fe(II)-cyclopentadienyl scaffolds. Their design and chemical properties are reviewed and correlated with their biological effects, in particular the key role that coligands play in the overall behavior of the complex.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Compuestos Ferrosos/farmacología , Neoplasias/tratamiento farmacológico , Rutenio/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Complejos de Coordinación/química , Complejos de Coordinación/uso terapéutico , Ciclopentanos/química , Dimetilsulfóxido/análogos & derivados , Dimetilsulfóxido/química , Dimetilsulfóxido/farmacología , Dimetilsulfóxido/uso terapéutico , Descubrimiento de Drogas , Compuestos Ferrosos/química , Compuestos Ferrosos/uso terapéutico , Humanos , Indazoles/química , Indazoles/farmacología , Indazoles/uso terapéutico , Terapia Molecular Dirigida , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/uso terapéutico , Unión Proteica , Rutenio/química , Rutenio/uso terapéutico , Compuestos de Rutenio
18.
J Inorg Biochem ; 153: 306-314, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26275470

RESUMEN

Searching for new prospective antitrypanosomal agents, three novel Ru(II)-cyclopentadienyl compounds, [Ru(η(5)-C5H5)(PPh3)L], with HL=bioactive 5-nitrofuryl containing thiosemicarbazones were synthesized and characterized in the solid state and in solution. The compounds were evaluated in vitro on the blood circulating trypomastigote form of Trypanosoma cruzi (Dm28c strain), the infective form of Trypanosoma brucei brucei (strain 427) and on J774 murine macrophages and human-derived EA.hy926 endothelial cells. The compounds were active against both parasites with IC50 values in the micromolar or submicromolar range. Interestingly, they are much more active on T. cruzi than previously developed Ru(II) classical and organometallic compounds with the same bioactive ligands. The new compounds showed moderate to very good selectivity towards the parasites in respect to mammalian cells. The global results point at [RuCp(PPh3)L2] (L2=N-methyl derivative of 5-nitrofuryl containing thiosemicarbazone and Cp=cyclopentadienyl) as the most promising compound for further developments (IC50T. cruzi=0.41µM; IC50T. brucei brucei=3.5µM). Moreover, this compound shows excellent selectivity towards T. cruzi (SI>49) and good selectivity towards T. brucei brucei (SI>6). In order to get insight into the mechanism of antiparasitic action, the intracellular free radical production capacity of the new compounds was assessed by ESR. DMPO (5,5-dimethyl-1-pirroline-N-oxide) spin adducts related to the bioreduction of the complexes and to redox cycling processes were characterized. In addition, DNA competitive binding studies with ethidium bromide by fluorescence measurements showed that the compounds interact with this biomolecule.


Asunto(s)
Antiprotozoarios/síntesis química , Proliferación Celular/efectos de los fármacos , Compuestos Organometálicos/síntesis química , Rutenio/química , Animales , Antiprotozoarios/química , Antiprotozoarios/toxicidad , Línea Celular , Línea Celular Tumoral , Chlorocebus aethiops , Células Endoteliales de la Vena Umbilical Humana , Humanos , Concentración 50 Inhibidora , Ratones , Compuestos Organometálicos/química , Compuestos Organometálicos/toxicidad , Tiosemicarbazonas/química , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos , Células Vero
19.
J Inorg Biochem ; 147: 165-76, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25958839

RESUMEN

The nuclease activity of VO(acac)2 (1, acac = acetylacetone) and its derivatives VO(hd)2 (2, hd = 3,5-heptanedione), VO(Cl-acac)2 (3, Cl-acac = 3-chloro-2,4-pentanedione), VO(Et-acac)2 (4, Et-acac = 3-ethyl-2,4-pentanedione) and VO(Me-acac)2 (5, Me-acac = 3-methyl-2,4-pentanedione), is studied by agarose gel electrophoresis, UV-visible spectroscopy, cyclic and square wave voltammetry and (51)V NMR. The mechanism is shown to be oxidative and associated with the formation of reactive oxygen species (ROS). Hydrolytic cleavage of the phosphodiester bond is also promoted by 1, but at much slower rate which cannot compete with the oxidative mechanism. The generation of ROS is much higher in the presence of phosphate buffer when compared with organic buffers and this was attributed to the formation of a mixed-ligand complex containing phosphate, (V(IV)O)(V(V)O)(acac)2(HnPO4(n-3)), presenting a quasi-reversible voltammetric behavior. The formation of this species was further observed by Electrospray Ionization Mass Spectrometry (ESI-MS). Phosphate being an essential species in most biological media, the importance of the formation of mixed-ligand species in other vanadium systems is emphasized.


Asunto(s)
ADN/química , Fosfatos/química , Compuestos de Vanadio/química , Hidrólisis , Oxidación-Reducción , Especies Reactivas de Oxígeno/química
20.
J Biol Inorg Chem ; 19(6): 853-67, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24562604

RESUMEN

A set of structurally related Ru(η(5)-C5H5) complexes with bidentate N,N'-heteroaromatic ligands have been evaluated as prospective metallodrugs, with focus on exploring the uptake and cell death mechanisms and potential cellular targets. We have extended these studies to examine the potential of these complexes to target cancer cell metabolism, the energetic-related phenotype of cancer cells. The observations that these complexes can enter cells, probably facilitated by binding to plasma transferrin, and can be retained preferentially at the membranes prompted us to explore possible membrane targets involved in cancer cell metabolism. Most malignant tumors present the Warburg effect, which consists in increasing glycolytic rates with production of lactate, even in the presence of oxygen. The reliance of glycolytic cancer cells on trans-plasma-membrane electron transport (TPMET) systems for their continued survival raises the question of their appropriateness as a target for anticancer drug development strategies. Considering the interesting findings that some anticancer drugs in clinical use are cytotoxic even without entering cells and can inhibit TPMET activity, we investigated whether redox enzyme modulation could be a potential mechanism of action of antitumor ruthenium complexes. The results from this study indicated that ruthenium complexes can inhibit lactate production and TPMET activity in a way dependent on the cancer cell aggressiveness and the concentration of the complex. Combination approaches that target cell metabolism (glycolytic inhibitors) as well as proliferation are needed to successfully cure cancer. This study supports the potential use of some of these ruthenium complexes as adjuvants of glycolytic inhibitors in the treatment of aggressive cancers.


Asunto(s)
Antineoplásicos/farmacología , Ciclopentanos/química , Compuestos Organometálicos/farmacología , Rutenio/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Conformación Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Relación Estructura-Actividad , Células Tumorales Cultivadas
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