RESUMEN

A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors of this series and best than the corresponding carboxylic acids (methyl sulfone 2: IC50 COX-1 = 0.04 and COX-2 = 0.10 µM, and naproxen: IC50 COX-1 = 11.3 and COX-2 = 3.36 µM). Interestingly, the inhibitory activity of compound 2 represents a significant improvement compared to that of the parent carboxylic compound, naproxen. Further support to the results were gained by the docking studies which suggested the ability of compound 2 and 7 to bind into COX enzyme with low binding free energies. The improvement of the activity of some sulfones compared to the carboxylic analogues would be performed through a change of the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen, as disclosed by molecular modeling studies. So, this study paves the way for further attention in investigating the participation of these new compounds in the pain inhibitory mechanisms. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs.

Asunto(s)

Antiinflamatorios no Esteroideos/farmacología , Antiulcerosos/farmacología , Dimetilsulfóxido/farmacología , Edema/tratamiento farmacológico , Úlcera Gástrica/tratamiento farmacológico , Sulfonas/farmacología , Ácido Acético , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiulcerosos/síntesis química , Antiulcerosos/química , Carragenina , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/química , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Humanos , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/química , Termodinámica

RESUMEN

Aldose reductase (AR) is an enzyme devoted to cell detoxification and at the same time is strongly involved in the aetiology of secondary diabetic complications and the amplification of inflammatory phenomena. AR is subjected to intense inhibition studies and dimethyl sulfoxide (DMSO) is often present in the assay mixture to keep the inhibitors in solution. DMSO was revealed to act as a weak but well detectable AR differential inhibitor, acting as a competitive inhibitor of the L-idose reduction, as a mixed type of non-competitive inhibitor of HNE reduction and being inactive towards 3-glutathionyl-4-hydroxynonanal transformation. A kinetic model of DMSO action with respect to differently acting inhibitors was analysed. Three AR inhibitors, namely the flavonoids neohesperidin dihydrochalcone, rutin and phloretin, were used to evaluate the effects of DMSO on the inhibition studies on the reduction of L-idose and HNE.

Asunto(s)

Aldehído Reductasa/antagonistas & inhibidores , Dimetilsulfóxido/farmacología , Inhibidores Enzimáticos/farmacología , Aldehído Reductasa/aislamiento & purificación , Aldehído Reductasa/metabolismo , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , Solventes/síntesis química , Solventes/química , Solventes/farmacología , Relación Estructura-Actividad

RESUMEN

PURPOSE: Recently, we reported the synthesis and characterization of two complexes of general formula cis-[Ru(S-DMSO)3(R-CO-CH=CH-R')Cl] (R = 2-hydroxyphenyl for both, R' = thiophene (1), 3-methyl thiophene (2)) that showed remarkable topoisomerase II inhibition and strong binding with DNA. The aim of this study was the investigation of cytotoxic properties of these complexes against a panel of human tumor cell lines, with elucidation of their anticancer mechanisms in HeLa cells. METHODS: Characterization of anticancer activity of the investigated ruthenium complexes 1 and 2 included analysis of cytotoxicity by MTT assay. Cell cycle phase disruption of HeLa cells treated with complexes 1 and 2 was analyzed by flow cytometry after propidium iodide (PI) staining. Annexin V-FITC/PI double staining and further flow cytometry analysis and acridine orange (AO)/ethidium bromide (EB) double staining and fluorescent microscopy were used to determine the apoptotic potential of the investigated ruthenium complexes. The inhibitory effect on gelatinases (MMP-2 and MMP-9) as an indication of possible antimetastatic potential was also analyzed using gelatine zymography. RESULTS: The 50% cell growth inhibition (IC50) values of the investigated complexes ranged between 22.9 and 76.8 µM, with complex 2 being more cytotoxic. Both complexes induced G2 phase cell cycle arrest and apoptosis in HeLa cells. Inhibitory effect of complex 2 on MMP-2 activity was detected. CONCLUSIONS: This work revealed the potential of the investigated Ru(II)-DMSO-chalcone complexes as anticancer agents with cytotoxic and pro-apoptotic activity and indicated complex 2 as leading compound for further chemical modifications and anticancer research.

Asunto(s)

Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Chalconas/farmacología , Dimetilsulfóxido/farmacología , Neoplasias/tratamiento farmacológico , Compuestos de Rutenio/farmacología , Inhibidores de Topoisomerasa II/farmacología , Proliferación Celular/efectos de los fármacos , Chalconas/síntesis química , Dimetilsulfóxido/análogos & derivados , Dimetilsulfóxido/síntesis química , Relación Dosis-Respuesta a Droga , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HeLa , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Estructura Molecular , Invasividad Neoplásica , Neoplasias/patología , Compuestos de Rutenio/síntesis química , Relación Estructura-Actividad , Factores de Tiempo , Inhibidores de Topoisomerasa II/síntesis química

RESUMEN

The work describes a new low-impact synthetic route to Pt(ii)-carboxylate complexes, a class of compounds provided with established anticancer activity. The process is based on the ligand substitution on [PtCO3(Me2SO-S)2] (), a new synthon that can be easily prepared in water with high yield, is stable as a solid, and is reactive in solution where all its ligands can be easily replaced. It reacts with acidic O-donors releasing CO2 as the only side-product, whose development also supplies a driving force toward the products. The substitution of carbonate led to new Pt-DMSO carboxylate complexes , while the total substitution of the ligands of complex gave new Pt-phosphino carboxylates in high yields. The X-ray crystal structures of complexes [Pt(d(-)-quinate-O,O')(Me2SO-S)2] (), [Pt(salicylate)(Me2SO-S)2] () and [Pt(salicylate)(PPh3)2] () were determined. The tests of the antiproliferative activity of complexes on two human tumoral cell lines, A2780 (cisplatin-sensitive) and SKOV-3 (cisplatin-resistant), showed that the PTA (PTA = 1,3,5-triaza-7-phosphaadamantane) complexes were the most active on both cell lines.

Asunto(s)

Antineoplásicos/síntesis química , Carbonatos/química , Ácidos Carboxílicos/síntesis química , Dimetilsulfóxido/química , Compuestos Organoplatinos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Carbonatos/síntesis química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética , Cristalografía por Rayos X , Dimetilsulfóxido/síntesis química , Humanos , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacología

RESUMEN

Reported in this paper is a very simple method for direct preparation of 4-substituted quinazoline derivatives from a reaction between substituted 2-aminobenzophenones and thiourea in the presence of dimethyl sulfoxide (DMSO). This is a unique complementary reaction system in which thiourea undergoes thermal decomposition to form carbodiimide and hydrogen sulfide, where the former reacts with 2-aminobenzophenone to form 4-phenylquinazolin-2(1H)-imine intermediate, whilst hydrogen sulfide reacts with DMSO to give methanethiol or other sulfur-containing molecule which then functions as a complementary reducing agent to reduce 4-phenylquinazolin-2(1H)-imine intermediate into 4-phenyl-1,2-dihydroquinazolin-2-amine. Subsequently, the elimination of ammonia from 4-phenyl-1,2-dihydroquinazolin-2-amine affords substituted quinazoline derivative. This reaction usually gives quinazoline derivative as a single product arising from 2-aminobenzophenone as monitored by GC/MS analysis, along with small amount of sulfur-containing molecules such as dimethyl disulfide, dimethyl trisulfide, etc. The reaction usually completes in 4-6 hr at 160 ºC in small scale but may last over 24 hr when carried out in large scale. The reaction product can be easily purified by means of washing off DMSO with water followed by column chromatography or thin layer chromatography.

Asunto(s)

Benzofenonas/síntesis química , Quinazolinas/síntesis química , Ácido Úrico/análogos & derivados , Técnicas de Química Sintética/métodos , Cromatografía/métodos , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/química , Disulfuros/síntesis química , Microondas , Compuestos de Sulfhidrilo/síntesis química , Sulfuros/síntesis química , Ácido Úrico/síntesis química

RESUMEN

The proprotein convertases PCSK8 and PCSK4 are, respectively, the 8th and 4th members of Ca(+2)-dependent serine endoprotease of Proprotein Convertase Subtilisin Kexin (PCSK) super family structurally related to the bacterial subtilisin and yeast kexin. The membrane bound PCSK8 (also called SKI-1 or S1P) is implicated in sterol regulation and lipid synthesis via its role in the maturation of human (h) SREBP-2. It also plays role in cartilage formation, bone mineralization, as well as viral pathogenesis. On the other hand, PCSK4 has been linked to mammalian fertilization and placenta growth. Owing to these findings, interest has grown to develop specific inhibitors against these enzymes for potential biochemical and therapeutic applications. In this study we developed two types of small molecule inhibitors of PCSK8 and PCSK4 and demonstrated their anti-proteolytic activities in vitro cell-free and in vitro cell culture systems. These are isocoumarinyl methyl sulfone derivatives and enediyne amino acid containing peptides. Our in vitro data suggested that one of the 7 sulfone derivatives (methyl phenyl sulfone) inhibited PCSK8 with inhibition constant Ki ∼255µM. It also blocked PCSK8-mediated processing of hSREBP-2 in HepG2 cell in a concentration-dependent manner. However all 7 iso-coumarinyl methyl sulfones inhibited htrypsin with IC50 ranging from 2 to 165µM. In contrast, all our designed enediynyl peptides inhibited PCSK8 and PCSK4 activity with Ki and IC50 in low µM or high nM ranges. All compounds exhibited competitive inhibition as indicated by their enzyme kinetic plots and observed dependence of IC50 value on substrate concentration. Our study confirmed that incorporation at the substrate cleavage site of 'Enediyne amino acid' generates potent inhibitors of PCSK8 and PCSK4. This represents a novel approach for future development of inhibitors of PCSK or other enzymes.

Asunto(s)

Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/farmacología , Diseño de Fármacos , Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Proproteína Convertasas/antagonistas & inhibidores , Sulfonas/síntesis química , Sulfonas/farmacología , Cumarinas/síntesis química , Cumarinas/química , Cumarinas/farmacología , Dimetilsulfóxido/química , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Oligopéptidos/química , Sulfonas/química

RESUMEN

With atmospheric oxygen as the oxidant, a novel copper(I)-catalyzed synthesis of aryl methyl sulfones from aryl halides and widely available DMSO is described. The procedure tolerates aryl halides with various functional groups (such as methoxy, acetyl, chloro, fluoro and nitro groups), which could afford aryl methyl sulfones in moderate to high yields. The copper-catalyzed aerobic oxidation and the cleavage/formation of C-S bond are the key steps for this transformation.

Asunto(s)

Cobre/química , Dimetilsulfóxido/química , Halógenos/química , Hidrocarburos Aromáticos/síntesis química , Sulfonas/síntesis química , Catálisis , Técnicas de Química Sintética/métodos , Dimetilsulfóxido/síntesis química , Hidrocarburos Aromáticos/química , Oxidación-Reducción , Sulfonas/química

RESUMEN

The complexes of type cis-[Ru(S-DMSO)(3)(R-CO-CH═CH-R')Cl] (R = 2-hydroxyphenyl for all, R' = phenyl 1, naphthyl 2, anthracenyl 3, thiophene 4, 3-methyl thiophene 5) are synthesized and characterized using spectroscopic (IR, (1)H and (13)C NMR, and UV-vis) and single crystal X-ray diffraction techniques. Their crystal structures show the formation of both intermolecular and intramolecular H-bonding. The molecular assembly of complex 5 using secondary interactions provides a butterfly structure. The binding of complexes with calf thymus DNA is monitored using UV-vis spectral titrations. The binding interaction of complexes 1, 2, and 3 with DNA increases with increasing conjugation of aromatic rings. However, complexes 4 and 5 interact with DNA strongly. The emission from ethidium bromide (EB) bound DNA recorded in phosphate buffer solution (pH = 7.2) decreases by incremental addition of solution of the complexes. The complexes 4 and 5 (100 µM) bind with the minor groove of DNA and cleave double-stranded pBR322 DNA significantly even in the absence of an activator. In the presence of H(2)O(2), they cleave supercoiled DNA via oxidative pathway even at lower concentration (20 µM). Both complexes 4 and 5 inhibit topoisomerase II activity with IC(50) values of 18 and 13. These values suggest that 4 and 5 are potential topoisomerase II inhibitors as compared to some of known inhibitors like novobiocin and etoposide.

Asunto(s)

Chalcona/farmacología , ADN/metabolismo , Desoxirribonucleasas/antagonistas & inhibidores , Dimetilsulfóxido/farmacología , Rutenio/farmacología , Inhibidores de Topoisomerasa II/farmacología , Animales , Bovinos , Chalcona/síntesis química , Chalcona/química , Cristalografía por Rayos X , División del ADN/efectos de los fármacos , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/química , Escherichia coli/enzimología , Etidio/metabolismo , Modelos Moleculares , Rutenio/química , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/química

RESUMEN

[ImH][trans-Ru(III)Cl(4)(DMSO)(Im)] (where DMSO is dimethyl sulfoxide and Im is imidazole) (NAMI-A) is an antimetastatic prodrug currently in phase II clinical trials. The mechanisms of action of this and related Ru-based anticancer agents are not well understood, but several cellular targets have been suggested. Although Ru has been observed to bind to DNA following in vitro NAMI-A exposure, little is known about Ru-DNA interactions in vivo and even less is known about how this or related metallodrugs might influence cellular RNA. In this study, Ru accumulation in cellular RNA was measured following treatment of Saccharomyces cerevisiae with NAMI-A. Drug-dependent growth and cell viability indicate relatively high tolerance, with approximately 40% cell death occurring at 6 h for 450 µM NAMI-A. Significant dose-dependent accumulation of Ru in cellular RNA was observed by inductively coupled plasma mass spectrometry measurements on RNA extracted from yeast treated with NAMI-A. In vitro, binding of Ru species to drug-treated model DNA and RNA oligonucleotides at pH 6.0 and 7.4 was characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in the presence and absence of the reductant ascorbate. The extent of Ru-nucleotide interactions increases slightly with lower pH and significantly in the presence of ascorbate, with differences in observed species distribution. Taken together, these studies demonstrate the accumulation of aquated and reduced derivatives of NAMI-A on RNA in vitro and in cellulo, and enhanced binding with nucleic acid targets in a tumorlike acidic, reducing environment. To our knowledge, this is also the first study to characterize NAMI-A treatment of S. cerevisiae, a genetically tractable model organism.

Asunto(s)

ADN/química , Dimetilsulfóxido/análogos & derivados , Compuestos Organometálicos/química , ARN/química , Rutenio/química , Rutenio/metabolismo , Saccharomyces cerevisiae/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Ácido Ascórbico/química , Supervivencia Celular/efectos de los fármacos , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/química , Dimetilsulfóxido/farmacología , Concentración de Iones de Hidrógeno , Hidrólisis , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacología , Rutenio/farmacología , Compuestos de Rutenio

RESUMEN

Se ha estudiado la farmacocinética de la absorción gastrointestinal del busulfán en dos grupos deratas, tras su administración por vía oral. La dosis influye en el valor de la constante de absorción(Ka) y en la concentración máxima normalizada (Cmax), presentando ambos parámetros unadisminución al aumentar la dosis de 0,5 a 5 mg. El empleo de un modelo aparentemonocompartimental con absorción de primer orden permite una adecuada descripción del perfil deniveles plasmáticos del antineoplásico. El dimetilsulfóxido, utilizado como disolvente del busulfán, nointerfiere en los parámetros farmacocinéticos orales del mismo(AU)

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We have studied the pharmacokinetics of gastrointestinal absorption of busulfan in two groups of rats,after oral administration. The dose effect on the value of the absorption constant (Ka) and thenormalized maximum concentration (Cmax), presenting both parameters decreased with increasingdose from 0.5 to 5 mg. Using a model with monocompartimental apparent first order absorptionallows an adequate description of the profile of plasma levels of antineoplastic. The dimethylsulfoxideused as busulfan solvent, does not interfere with oral pharmacokinetic parameters of it(AU)

Asunto(s)

Animales , Masculino , Femenino , Ratas , Busulfano/farmacocinética , Absorción Intestinal , Dimetilsulfóxido/farmacocinética , Dimetilsulfóxido/química , Antineoplásicos/farmacocinética , Cromatografía , Busulfano/farmacología , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/farmacología , 28599 , Análisis de Varianza

RESUMEN

Reaction of 3-pyridinehydroxamic acid and 4-pyridinehydroxamic acid (3-pyha and 4-pyha) with either [NBu4][RuCl4(dmso-S)2] or [(dmso)2H][RuCl4(dmso-S)2] (dmso is dimethyl sulfoxide) in acetone afforded three new ruthenium(III) dimethyl sulfoxide pyridinehydroxamic acid complexes: [NBu4][trans-RuCl4(dmso-S)(4-pyha)] x CH3CO CH3 (1), [3-pyhaH][trans-RuCl4(dmso-S)(3-pyha)] (2) and [4-pyhaH][trans-RuCl4(dmso-S)(4-pyha)] (3). The solid-state structure of [NBu4][trans-RuCl4(dmso-S)(4-pyha)] x CH3COCH3 (1) was determined by X-ray crystallography. 2 and 3 were pharmacologically evaluated for their in vitro cytotoxicity, their ability to inhibit cell invasion and their gelatinase activity. 2 and 3 were devoid of cytotoxicity against the cell lines tested. 2 inhibited invasion of the highly invasive MDA-MB-231 cells to a much greater extent than 3. Contrary to expectations, neither 2 nor 3 had any inhibitory effect on matrix metalloproteinase (MMP) production and/or activity and in fact 3 was found to enhance the production and/or activity of both MMP-2 and MMP-9.

Asunto(s)

Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/farmacología , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Dimetilsulfóxido/química , Gelatinasas/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Invasividad Neoplásica/patología , Metástasis de la Neoplasia/patología , Compuestos Organometálicos/química

RESUMEN

Imidazolium [trans-tetrachloro(1H-imidazole)(S-dimethylsulfoxide)ruthenate(III)] (NAMI-A) and indazolium [trans-tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) are the most promising ruthenium complexes for anticancer chemotherapy. In this study, the azole ligand of NAMI-A was systematically varied (from imidazole of NAMI-A to indazole, 1,2,4-triazole, 4-amino-1,2,4-triazole, and 1-methyl-1,2,4-triazole), and the respective complexes were evaluated with regard to the rate of aquation and protein binding, redox potentials, and cytotoxicity by means of capillary zone electrophoresis, electrospray ionization mass spectrometry, cyclic voltammetry, and colorimetric microculture assays. Stability studies demonstrated low stability of the complexes at pH 7.4 and 37 degrees C and a high reactivity toward proteins (binding rate constants in the ranges of 0.02-0.34 and 0.01-0.26 min-1 for albumin and transferrin, respectively). The redox potentials (between 0.25 and 0.35 V) were found to be biologically accessible for activation of the complexes in the tumor, and the indazole-containing compound shows the highest antiproliferative activity in vitro.

Asunto(s)

Antineoplásicos/síntesis química , Dimetilsulfóxido/análogos & derivados , Imidazoles/síntesis química , Compuestos Organometálicos/síntesis química , Rutenio , Triazoles/síntesis química , Albúminas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Colorimetría , Cristalografía por Rayos X , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/química , Dimetilsulfóxido/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Electroforesis Capilar , Humanos , Concentración de Iones de Hidrógeno , Imidazoles/química , Imidazoles/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Oxidación-Reducción , Potenciometría , Unión Proteica , Compuestos de Rutenio , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Transferrina/química , Triazoles/química , Triazoles/farmacología , Agua/química

Asunto(s)

Atmósfera/química , Dimetilsulfóxido/química , Oxígeno/química , Sulfuros/química , Dimetilsulfóxido/síntesis química , Radicales Libres/síntesis química , Radicales Libres/química , Cinética , Modelos Químicos , Oxidación-Reducción , Sulfuros/síntesis química , Temperatura

RESUMEN

NAMI-A, i. e. (imH)[trans-RuCl(4)(dmso-S)(im)] (im = imidazole, dmso = dimethylsulfoxide), is a Ru(III) complex that, after extensive preclinical investigations that evidenced its remarkable and specific activity against metastases, has recently and successfully completed a Phase I trial (first ruthenium complex ever to reach clinical testing). This review article, after a brief summary of the main chemical and pharmacological aspects of NAMI-A, focuses on the development of new classes of ruthenium complexes originated from the NAMI-A frame. In particular, the chemical and biological features of the following classes of compounds will be treated: i) NAMI-A-type complexes, derived from NAMI-A by changing the nature of the N-ligand, ii) dinuclear NAMI-A-type compounds containing heterocyclic bridging N-N ligands, iii) new Ru-dmso nitrosyls broadly derived from NAMI-A-type complexes. Several of these new compounds were found to have antimetastatic activity comparable to, or even better than, NAMI-A; however, the nature of the target(s) responsible for the antimetastatic activity remains unclear. Common to any type of NAMI-A-type compound, both monomeric and dimeric, cell cytotoxicity (which is generally very low) is not sufficient to explain their potent and peculiar antitumor activity. All active NAMI-A-type compounds share the capacity to modify important parameters of metastasis such as tumor invasion, matrix metallo proteinases activity and cell cycle progression.

Asunto(s)

Antineoplásicos , Dimetilsulfóxido , Dimetilsulfóxido/análogos & derivados , Metástasis de la Neoplasia/prevención & control , Compuestos Organometálicos , Rutenio/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/química , Dimetilsulfóxido/farmacología , Humanos , Ligandos , Conformación Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Compuestos de Rutenio

RESUMEN

Two ruthenium(III) complexes bearing the thiazole ligand, namely, thiazolium (bisthiazole) tetrachlororuthenate (I, TzICR) and thiazolium (thiazole, DMSO) tetrachlororuthenate (II, TzNAMI) were prepared and characterized. The crystal structures of both complexes were solved by X-ray diffraction methods and found to match closely those of the corresponding imidazole complexes. The behavior in aqueous solution of bothTzICR and TzNAMI was analyzed spectroscopically. The time-dependent spectrophotometric profiles resemble closely those of the related ICR and NAMI-A anticancer compounds, respectively. It is observed that replacement of imidazole with thiazole, a less basic ligand, produces a significant decrease of the ligand exchange rates in the case of the NAMI-like compound. The main electrochemical features of these ruthenium(III) thiazole complexes were determined and compared to those of ICR and NAMI-A. Moreover, some preliminary data were obtained on their biological properties. Notably, both complexes exhibit higher reactivity toward serum albumin than toward calf thymus DNA; cytotoxicity is negligible in line with expectations. A more extensive characterization of the pharmacological properties in vivo is presently in progress.

Asunto(s)

Antineoplásicos/química , Compuestos Organometálicos/química , Rutenio/química , Tiazoles/química , Algoritmos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Cristalografía por Rayos X , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/química , Dimetilsulfóxido/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Cinética , Modelos Moleculares , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Estereoisomerismo , Tiazoles/síntesis química , Tiazoles/farmacología , Células Tumorales Cultivadas

RESUMEN

The ability of two structurally different ruthenium complexes to interfere with the catalytic activity of topoisomerase II was studied to elucidate their molecular mechanism of action and relative antineoplastic activity. The first complex, [RuCl2(C6H6)(dmso)], could completely inhibit DNA relaxation activity of topoisomerase II and form a drug-induced cleavage complex. This strongly suggests that the drug interferes with topoisomerase II activity by cleavage complex formation. The bi-directional binding of [RuCl2(C6H6)(dmso)] to DNA and topoisomerase II was verified by immunoprecipitation experiments which confirmed the presence of DNA and ruthenium in the cleavage complex. The second complex, Ruthenium Salicylaldoxime, could not inhibit topoisomerase II relaxation activity appreciably and also could not induce cleavage complex formation, though its DNA-binding characteristics and antiproliferation activity were almost comparable to those of [RuCl2(C6H6)(dmso)]. The results suggest that the difference in ligands and their orientation around a metal atom may be responsible for topoisomerase II poisoning by the first complex and not by the second. A probable mechanism is proposed for [RuCl2(C6H6)(dmso)], where the ruthenium atom interacts with DNA and ligands of the metal atom form cross-links with topoisomerase II. This may facilitate the formation of a drug-induced cleavage complex.

Asunto(s)

Dimetilsulfóxido/farmacología , Compuestos Organometálicos/farmacología , Compuestos de Rutenio/farmacología , Inhibidores de Topoisomerasa II , Adenosina Trifosfatasas/química , Animales , Antineoplásicos/farmacología , Catálisis/efectos de los fármacos , ADN/química , ADN Ligasas/química , Dimetilsulfóxido/síntesis química , Interacciones Farmacológicas , Activación Enzimática/efectos de los fármacos , Estabilidad de Enzimas/efectos de los fármacos , Inhibidores de Crecimiento/farmacología , Ligandos , Sustancias Macromoleculares , Compuestos Organometálicos/síntesis química , Ratas , Compuestos de Rutenio/síntesis química , Células Tumorales Cultivadas

RESUMEN

Dimethylsulfoxide (DMSO) formed a ternary complex when mixed with a Zn-3, 5-diisopropylsalicylate complex of unknown structure. The structure of this new ternary complex was characterized in an initial effort to understand the nature of this compound. Since the original complex is known to have anticonvulsant activity, the new ternary complex was also examined for anticonvulsant activity. The original complex was examined for inhibition of the polymorphonuclear leukocyte (PMNL) respiratory burst in an effort to mechanistically account for zinc complex mediated anticonvulsant activity. Dissolving the structurally unknown complex in DMSO gave crystals of a characterizable complex with an empirical formula C30H46O8S2Zn. Crystallographic data: P 1, Z = 2, a = 8.06(1), b = 12.452(2), c = 17.951(2) A, alpha = 74.42(l), beta = 77.07(1), gamma = 89.50(1) degree. The structure was refined to R = 0.03, RW = 0.04 for 3815 independent reflections with I > 2 sigma(I). This complex is mononuclear, with two 3,5-diisopropylsalicylate ligands and two bonded DMSO ligands, Zn(II)(3,5-DIPS)2(DMSO)2, Zn(II) is coordinate covalently bonded to four O atoms in a strongly distorted tetrahedral arrangement. Each DMSO ligates via its sulfoxide O atom while each 3,5-diisopropylsalicylate ligand is monodentate The non-ligating carbonyl O atom of each 3,5-DIPS is free except for an intramolecular hydrogen bond from the hydroxy group of the same ligand. Both 3,5-DIPS acid and Zn(II)(3,5-DIPS)2(DMSO)2 were examined for anticonvulsant activity in the Maximal Electroshock (MES) and Metrazol (MET) models of seizures and found to prevent both types of seizures. The Zn complex was qualitatively and quantitatively more effective than treatment with the free ligand. The influence of a Zn 3,5-DIPS complex and of the ligand 3,5-DIPS on PMNL oxidative metabolism was also studied to help understand the mechanism of anticonvulsant activity of these compounds. A dose-related and significant decrease in chemiluminescent (CL) response to opsonized Zymosan was observed, and the Zn complex was significantly more effective than the free ligand. It is concluded that mononuclear Zn complexes have anticonvulsant activity in Grand Mal and Petit Mal models of seizure possibly due to inhibition of the synthesis of superoxide or down-regulation of Nitric Oxide Synthase in activated phagocytic cells of the central nervous system.

Asunto(s)

Anticonvulsivantes/química , Dimetilsulfóxido/análogos & derivados , Neutrófilos/fisiología , Compuestos Organometálicos/química , Convulsiones/prevención & control , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Cristalografía por Rayos X , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/química , Dimetilsulfóxido/farmacología , Electrochoque , Mediciones Luminiscentes , Masculino , Ratones , Ratones Endogámicos , Modelos Moleculares , Neutrófilos/efectos de los fármacos , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Pentilenotetrazol , Ratas , Ratas Sprague-Dawley , Estallido Respiratorio/efectos de los fármacos , Convulsiones/inducido químicamente

RESUMEN

A new technique is described that permits the permethylation of acylated peptides at the 2-10 nmol level. The presence of up to 400 micrograms of sodium dodecyl sulphate per sample does not affect the reaction yields. The technique, which is a miniaturization of the widely used methyl iodide/dimethylsulphinyl carbanion procedure, employs a layer of hexane to exclude moisture and oxygen from the reaction mixture. Analysis of the peptide derivatives by combined g.l.c.--mass spectrometry permits amino acid sequence information to be obtained. In addition to studies of digests of a model substrate (glucagon), the new permethylation technique has been used to identify a peptide of interest from a digest of a cytochrome and to define the N-termini of two proteins at the 5 nmol level.

Asunto(s)

Fragmentos de Péptidos , Acetilación , Secuencia de Aminoácidos , Dimetilsulfóxido/síntesis química , Cromatografía de Gases y Espectrometría de Masas , Glucagón , Interferón gamma , Métodos , Metilación

Asunto(s)

Dimetilsulfóxido , Anomalías Inducidas por Medicamentos/etiología , Absorción , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Anuros , Transporte Biológico/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Dimetilsulfóxido/sangre , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/metabolismo , Dimetilsulfóxido/farmacología , Dimetilsulfóxido/toxicidad , Dimetilsulfóxido/orina , Electrólitos/metabolismo , Oftalmopatías/inducido químicamente , Cobayas , Dosificación Letal Mediana , Ratones , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/metabolismo , Dolor , Conejos , Ratas , Piel/efectos de los fármacos , Absorción Cutánea

Asunto(s)

Dimetilsulfóxido/farmacología , Fenómenos Químicos , Química Orgánica , Química Farmacéutica , Química Física , Dimetilsulfóxido/análisis , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/uso terapéutico , Indicadores y Reactivos , Fenómenos Químicos Orgánicos , Excipientes Farmacéuticos