RESUMEN
A novel mononuclear palladium complex with 2-(3,5-di-tert-butyl-2-hydroxyphenyl amino) benzonitrile as a non-innocent ligand (abbreviated as PdIIL2 NIS) was synthesized, and characterized by IR, UV-Vis, 1H and 13C NMR spectroscopies and elemental analysis. The crystal structure clearly showed that the metal center was in a square planar environment. The bond lengths obtained from X-ray structure analysis revealed that both ligands are in the o-iminobenzosemiquinone radical form. The neutral complex showed strong absorptions in the NIR region, corresponding to the ILCT (intra-ligand charge transfer). Catalytic tests performed for the coupling reaction of terminal alkynes showed that the palladium PdIIL2 NIS complex acts as a highly effective catalyst for the base-free C-C coupling reactions, leading to diyne derivatives with excellent yields. The PdIIL2 NIS complex in ethanol, as a green solvent, is demonstrated to be an exceptionally active phosphine-free catalyst for the Suzuki reaction of aryl iodides and bromides. The reaction can be carried out under mild conditions (room temperature) with high yields without using a microwave or phosphine ligands. This catalyst exhibits an interesting application of redox non-innocent ligands, the electron reservoir behavior, which makes it needless to use additional reagents. The theoretical calculation provides more details about the complex structure, molecular orbitals, and electronic state.
RESUMEN
The platinum(II) complexes of general formula [PtCl2(dstp)(S-donor)] were dstp 5,7-dimethyl-1,2,4-triazolo[1,5-a]-pyrimidine (dmtp), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp), 5-methyl-7-isobutyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp) or 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp), whereas S-tetrahydrothio-phene-1-oxide (TMSO) or diphenyl sulfoxide (DPSO) were synthesized in a one-pot reaction. Here, we present experimental data (1H, 13C, 15N, 195Pt NMR, IR, X-ray) combined with density functional theory (DFT) computations to support and characterize structure-spectra relationships and determine the geometry of dichloride platinum(II) complexes with selected triazolopyrimidines and sulfoxides. Based on the experimental and theoretical data, factors affecting the stability of platinum(II) complexes have been determined.
Asunto(s)
Antineoplásicos , Platino (Metal) , Antineoplásicos/química , Derivados del Benceno , Línea Celular Tumoral , Óxidos , Platino (Metal)/química , Pirimidinas , Sulfóxidos , Tiofenos , Triazoles/químicaRESUMEN
A series of new chiral benzisoselenazol-3(2H)-ones and their corresponding diselenides bearing an o-amido function substituted on the nitrogen atom with various aliphatic and aromatic moieties were synthesized. All derivatives representing pairs of enantiomers or diastereoisomers were obtained to thoroughly evaluate the three-dimensional structure-activity correlation. First, bensisoselenazol-3(2H)-ones were synthesized by reacting 2-(chloroseleno)benzoyl chloride with an appropriate enantiomerically pure amine. Then, the Se-N bond was cleaved by a reduction-oxidation procedure using sodium borohydride and then air oxidation to obtain the corresponding diselenides. All derivatives were tested as antioxidants and anticancer agents. In general, the diselenides were more reactive peroxide scavengers, with the highest activity observed for 2,2'-diselenobis[N-(1S,2S)-(-)-trans-2-hydroksy-1-indanylbezamide]. The most cytotoxic derivative towards human promyelocytic leukemia HL-60 and breast cancer MCF-7 cell lines was N-[(1S,2R)-(-)-cis-2-hydroksy-1-indanyl]-1,2-benzizoselenazol-3(2H)-one. The structure-activity relationship of the obtained organoselenium derivatives was discussed.
RESUMEN
Adenylate kinases (AK) play a pivotal role in the regulation of cellular energy. The aim of our work was to achieve the overproduction and purification of AKs from two groups of bacteria and to determine, for the first time, the comprehensive biochemical and kinetic properties of adenylate kinase from Gram-negative Aquifex aeolicus (AKaq) and Gram-positive Geobacillus stearothermophilus (AKst). Therefore we determined KM and Vmax values, and the effects of temperature, pH, metal ions, donors of the phosphate groups and inhibitor Ap5A for both thermophilic AKs. The kinetic studies indicate that both AKs exhibit significantly higher affinity for substrates with the pyrophosphate group than for adenosine monophosphate. AK activation by Mg2+ and Mn2+ revealed that both ions are efficient in the synthesis of adenosine diphosphate and adenosine triphosphate; however, Mn2+ ions at 0.2-2.0 mmol/L concentration were more efficient in the activation of the ATP synthesis than Mg2+ ions. Our research demonstrates that zinc ions inhibit the activity of enzymes in both directions, while Ap5A at a concentration of 10 µmol/L and 50 µmol/L inhibited both enzymes with a different efficiency. Sigmoid-like kinetics were detected at high ATP concentrations not balanced by Mg2+, suggesting the allosteric effect of ATP for both bacterial AKs.
Asunto(s)
Adenosina Trifosfato/metabolismo , Adenilato Quinasa/metabolismo , Difosfatos/metabolismo , Geobacillus stearothermophilus/enzimología , Zinc/metabolismo , Adenilato Quinasa/química , Aquifex/enzimología , CinéticaRESUMEN
Within the broad group of Fe non-heme oxidases, our attention was focused on the catechol 1,2- and 2,3-dioxygenases, which catalyze the oxidative cleavage of aromatic rings. A large group of Fe complexes with N/O ligands, ranging from N3 to N2O2S, was developed to mimic the activity of these enzymes. The Fe complexes discussed in this work can mimic the intradiol/extradiol catechol dioxygenase reaction mechanism. Electronic effects of the substituents in the ligand affect the Lewis acidity of the Fe center, increasing the ability to activate dioxygen and enhancing the catalytic activity of the discussed biomimetic complexes. The ligand architecture, the geometric isomers of the complexes, and the substituent steric effects significantly affect the ability to bind the substrate in a monodentate and bidentate manner. The substrate binding mode determines the preferred mechanism and, consequently, the main conversion products. The preferred mechanism of action can also be affected by the solvents and their ability to form the stable complexes with the Fe center. The electrostatic interactions of micellar media, similar to SDS, also control the intradiol/extradiol mechanisms of the catechol conversion by discussed biomimetics.
RESUMEN
Statins are the most effective cholesterol-lowering drugs. They also exert many pleiotropic effects, including anti-cancer and cardio- and neuro-protective. Numerous nano-sized drug delivery systems were developed to enhance the therapeutic potential of statins. Studies on possible interactions between statins and human proteins could provide a deeper insight into the pleiotropic and adverse effects of these drugs. Adenylate kinase (AK) was found to regulate HDL endocytosis, cellular metabolism, cardiovascular function and neurodegeneration. In this work, we investigated interactions between human adenylate kinase isoenzyme 1 (hAK1) and atorvastatin (AVS), fluvastatin (FVS), pravastatin (PVS), rosuvastatin (RVS) and simvastatin (SVS) with fluorescence spectroscopy. The tested statins quenched the intrinsic fluorescence of hAK1 by creating stable hAK1-statin complexes with the binding constants of the order of 104 M-1. The enzyme kinetic studies revealed that statins inhibited hAK1 with significantly different efficiencies, in a noncompetitive manner. Simvastatin inhibited hAK1 with the highest yield comparable to that reported for diadenosine pentaphosphate, the only known hAK1 inhibitor. The determined AK sensitivity to statins differed markedly between short and long type AKs, suggesting an essential role of the LID domain in the AK inhibition. Our studies might open new horizons for the development of new modulators of short type AKs.
Asunto(s)
Adenilato Quinasa/química , Geobacillus stearothermophilus/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/química , Adenilato Quinasa/metabolismo , Secuencia de Aminoácidos , Atorvastatina/química , Dicroismo Circular , Fluvastatina/química , Geobacillus stearothermophilus/química , Geobacillus stearothermophilus/enzimología , Geobacillus stearothermophilus/genética , Humanos , Concentración 50 Inhibidora , Isoenzimas/química , Cinética , Ligandos , Simulación del Acoplamiento Molecular , Pravastatina/química , Unión Proteica , Proteínas Recombinantes , Rosuvastatina Cálcica/química , Alineación de Secuencia , Simvastatina/química , Espectrometría de Fluorescencia , Espectrofotometría , Electricidad Estática , TemperaturaRESUMEN
The six-coordinated bis-o-iminosemiquinone complex, NiL2 BIS, in which LBIS is the o-iminosemiquinone 1-electron oxidized form of the tridentate o-aminophenol benzoxazole-based ligand H2LBAP, was synthesized and characterized. The crystal structure of the complex reveals octahedral geometry with a NiN4O2 coordination sphere in which Ni(ii) has been surrounded by two tridentate LBIS ligands. This compound exhibits (S Ni = 1) with both spin and orbital contribution to the magnetic moment and antiferromagnetic coupling between two electrons on two LBIS ligands which results in a triplet spin ground state (S = 1). The electronic transitions and the electrochemical behavior of this open-shell molecule are presented here, based on experimental observations and theoretical calculations. The electrochemical behavior of NiL2 BIS was investigated by cyclic voltammetry and indicates ligand-centered redox processes. Three-component coupling of aldehydes, amines and alkynes (A3-coupling) was studied in the presence of the NiL2 BIS complex, and the previously reported four-coordinated bis-o-iminosemiquinone NiL2 NIS. Furthermore, among these two o-iminobenzosemiquinonato(1-) complexes of Ni(ii) (NiL2 NIS and NiL2 BIS), NiL2 NIS was found to be an efficient catalyst in A3-coupling at 85 °C under solvent-free conditions and can be recovered and reused for several cycles with a small decrease in activity.
RESUMEN
Herein, we present dicarboxylate platinum(II) complexes of the general formula [Pt(mal)(DMSO)(L)] and [Pt(CBDC)(DMSO)(L)], where L is dbtp 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine) or ibmtp (7-isobutyl-5-methyl-1,2,4- triazolo[1,5-a]pyrimidine), as prospective prodrugs. The platinum(II) complexes were synthesized in a one-pot reaction between cis-[PtCl2(DMSO)2], silver malonate or silver cyclobutane-1,1-dicarboxylate and triazolopyrimidines. All platinum(II) compounds were characterized by FT-IR, and 1H, 13C, 15N and 195Pt NMR; and their square planar geometries with one monodentate N(3)-bonded 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidine, one S-bonded molecule of dimethyl sulfoxide and one O,O-chelating malonato (1, 2) or O,O-chelating cyclobutane-1,1-dicarboxylato (3, 4) was determined. Additionally, [Pt(CBDC)(dbtp)(DMSO)] (3) exhibited (i) substantial in vitro cytotoxicity against the lung adenocarcinoma epithelial cell line (A549) (IC50 = 5.00 µM) and the cisplatin-resistant human ductal breast epithelial tumor cell line (T47D) (IC50 = 6.60 µM); and (ii) definitely exhibited low toxicity against normal murine embryonic fibroblast cells (BALB/3T3).
RESUMEN
Two types of ruthenium(ii) complexes containing 1,2,4-triazolo[1,5-a]pyrimidines of the general formulas [RuCl2(dmso)3(L)] ((1)-(3)) and [RuCl2(dmso)2(L)2] ((4)-(6)), where L represents 1,2,4-triazolo[1,5-a]pyrimidine (tp for (1)), 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp for (2)), 7-isobutyl-5-methyl-1,2,4-trizolo[1,5-a]pyrimidine (ibmtp for (3)), 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine (detp for (4)), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp for (5)) and 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp for (6)), have been synthesized and characterized by elemental analysis, infrared, multinuclear magnetic resonance spectroscopic techniques (1H, 13C, and 15N), and X-ray (for (3), (4), and (5)). All these complexes have been thoroughly screened for their in vitro cytotoxicity against melanoma cell lines A375 and Hs294T, indicating cis,cis,cis-[RuCl2(dbtp)2(dmso)2] (5) as the most active representative, in addition to being non-toxic to normal human fibroblasts (NHDF) and not inducing hemolysis of human erythrocytes. In order to develop an intravenous formulation for (5), liposomes composed of soybean phosphatidylcholine (SPC), cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000) were prepared and subsequently characterized. (5)-Loaded liposomes, with spherical morphology, assessed by transmission electron microscope (TEM), exhibited satisfactory encapsulation efficiency and stability. In in vitro experiments, PEG-modified (5)-loaded liposomes were more effective (10-fold) than free (5) for growth inhibition of both human melanoma cell lines. Furthermore, such an approach resulted in the reduction of cancer cell viability that was even 10-fold greater than that observed for free cisplatin.
Asunto(s)
Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Liposomas/química , Melanoma/patología , Nanoestructuras/química , Pirimidinas/química , Rutenio/química , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacología , Cápsulas , Línea Celular Tumoral , Complejos de Coordinación/administración & dosificación , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Triazoles/químicaRESUMEN
In this study, a novel Mn(iii)-Schiff base complex was synthesized and characterized. The structure of this complex was determined to be a deformed octahedral coordination sphere by single-crystal X-ray diffraction analysis. The Mn(iii)-Schiff base complex was supported on silica-coated iron magnetic nanoparticles via axial coordination by one-step complex anchoring to produce a heterogenized nanocatalyst. After this, the complex was characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), thermogravimetric analysis (TGA), vibrating sample magnetometry (VSM), and powder X-ray diffraction (XRD). Moreover, atomic absorption spectroscopy was used to determine the amount of the loaded metal. The heterogenized nanocatalyst effectively catalyzed the oxidation of a broad range of sulfides and alkenes with H2O2 in the presence of a glassy carbon electrode, applying voltage to the reaction mixture. The results showed that the application of a potential to the reaction mixture could significantly decrease the reaction time when compared with the case of similar chemical oxidation reactions. In addition, an excellent value of turnover frequency (17 750 h-1) was achieved for the electrochemical oxidation of styrene. Moreover, the nanocatalyst showed good recoverability without significant loss of its activity within six successive runs in the electrochemical oxidation of methyl phenyl sulfide and cyclooctene. The electrochemical properties and stability of Fe3O4@SiO2-[MnL(OAc)] were investigated by cyclic voltammetry measurements and chronoamperometry technique.
RESUMEN
A new Ni(ii) complex, was synthesized from the reaction of a non-innocent o-aminophenol ligand, and Ni(OAc)2. The crystal structure of NiIIL2 NIS (in which, IS stands for iminosemiquinone radical ligand with cyanide (shown by N in NIS) substituent on phenolate rings) exhibits the square planar environment of Ni(ii). The complex has been crystalized in the monoclinic system and Ni(ii) was surrounded by two oxygen and two nitrogen atoms of two ligands. Variable-temperature magnetic susceptibility measurement for crystalline samples of complex shows the effective magnetic moment per molecule (µ eff) of near zero and the diamagnetic nature of the complex (S = 0) which emphasize that strong antiferromagnetic coupling prevailed between the two unpaired electrons of LNIS ligands and Ni(ii) high spin electrons. The complex is EPR silent which confirms the diamagnetic character of the Ni(ii) complex. Electrochemical measurement (CV) indicates the redox-active character of ligand and metal. NiIIL2 NIS complex proved to be effective for free metal- or base counterpart homocoupling of phenyl acetylene at room temperature. To the best of our knowledge, this is the first example of using Ni(ii) complex without using any reducing agent due to the promotion ancillary effect of non-innocent o-aminophenol ligand which acts as an "electron reservoir" and can reversibly accept and donate electrons in the catalytic cycle. The theoretical calculation confirms the magnetostructure, electronic spectrum and confirmed the suggested mechanism of phenyl acetylene homocoupling with emphasis on the role of non-innocent ligand electro-activity and the effect of ligand substituent on the efficiency and stability of the complex.
RESUMEN
We report a new mononuclear molybdenum(iv) complex, MoOLBISLSQ, in which LSQ (2,4-di-tert-butyl o-semibenzoquinone ligand) has been prepared from the reaction of the o-iminosemibenzoquinone form of a tridentate non-innocent benzoxazole ligand, LBIS, and MoO2(acac)2. The complex was characterized by X-ray crystallography, elemental analysis, IR and UV-vis spectroscopy and magnetic susceptibility measurements. The crystal structure of MoOLBISLSQ revealed a distorted octahedral geometry around the metal centre, surrounded by one O and two N atoms of LBIS and two O atoms of LSQ. The effective magnetic moment (µ eff) of MoOLBISLSQ decreased from 2.36 to 0.2 µB in the temperature range of 290 to 2 K, indicating a singlet ground state caused by antiferromagnetic coupling between the metal and ligand centred unpaired electrons. Also, the latter led to the EPR silence of the complex. Cyclic voltammetry (CV) studies indicate both ligand and metal-centered redox processes. MoOLBISLSQ was applied as a catalyst for the oxidative cleavage of cyclohexene to adipic acid and selective oxidation of sulfides to sulfones with aqueous hydrogen peroxide.
RESUMEN
A method of purifying cyclododecyl 2,4-dihydroxybenzoate as a potential replacement template molecule for preparation of molecularly-imprinted polymers for isolation of zearalenone in urine was developed. Full physicochemical characteristics of cyclododecyl 2,4-dihydroxybenzoate for the first time included crystallographic analysis and molecular modelling, which made possible the determination of the similarity between the cyclododecyl 2,4-dihydroxybenzoate and zearalenone molecules. The obtained molecularly-imprinted polymers show very high in vitro selectivity towards zearalenone due to specific interactions (e.g., hydrogen bonding, molecular recognition interaction). The achieved extraction recovery exceeds 94% at the tested concentration levels (20â»500 ng·mL-1) with a relative standard deviation below 2%. Immunosorbents were found to have lower recoveries (below 92.5%) and RSD value between 2 and 4% for higher concentrations of the studied substance (400 ng·mL-1).
Asunto(s)
Cicloparafinas/química , Hidroxibenzoatos/química , Impresión Molecular , Micotoxinas/orina , Polímeros/química , Zearalenona/química , Adsorción , Calibración , Cristalografía por Rayos X , Teoría Funcional de la Densidad , Humanos , Enlace de Hidrógeno , Concentración de Iones de Hidrógeno , Cinética , Límite de Detección , Espectroscopía de Resonancia Magnética , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , TemperaturaRESUMEN
Etiology of the Alzheimer's disease (AD) is not fully understood. Different pathological processes are considered, such as amyloid deposition, tau protein phosphorylation, oxidative stress (OS), metal ion disregulation, or chronic neuroinflammation. Purinergic signaling is involved in all these processes, suggesting the importance of nucleotide receptors (P2X and P2Y) and adenosine receptors (A1, A2A, A2B, A3) present on the CNS cells. Ecto-purines, ecto-pyrimidines, and enzymes participating in their metabolism are present in the inter-cellular spaces. Accumulation of amyloid-ß (Aß) in brain induces the ATP release into the extra-cellular space, which in turn stimulates the P2X7 receptors. Activation of P2X7 results in the increased synthesis and release of many pro-inflammatory mediators such as cytokines and chemokines. Furthermore, activation of P2X7 leads to the decreased activity of α-secretase, while activation of P2Y2 receptor has an opposite effect. Simultaneous inhibition of P2X7 and stimulation of P2Y2 would therefore be the efficient way of the α-secretase activation. Activation of P2Y2 receptors present in neurons, glia cells, and endothelial cells may have a positive neuroprotective effect in AD. The OS may also be counteracted via the purinergic signaling. ADP and its non-hydrolysable analogs activate P2Y13 receptors, leading to the increased activity of heme oxygenase, which has a cytoprotective activity. Adenosine, via A1 and A2A receptors, affects the dopaminergic and glutaminergic signaling, the brain-derived neurotrophic factor (BNDF), and also changes the synaptic plasticity (e.g., causing a prolonged excitation or inhibition) in brain regions responsible for learning and memory. Such activity may be advantageous in the Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Receptores Purinérgicos P1/metabolismo , Receptores Purinérgicos/metabolismo , Animales , Humanos , Neuroglía/metabolismo , Neuronas/metabolismoRESUMEN
Redox interplay between a ligand and a metal can provide a profound driving force for the promotion of unprecedented reactions. This work presents an intriguing water-assisted oxidative transformation of imine to amide with no formal change in the metal oxidation state in the copper and nickel complexes of an aminophenol ligand versus a zinc analogue.
RESUMEN
Tropical diseases currently constitute a major health problem and thus a challenge in the field of drug discovery. The current treatments show serious disadvantages due to cost, toxicity, long therapy duration and resistance, and the use of metal complexes as chemotherapeutic agents against these ailments appears to be a very attractive alternative. Herein, we describe three newly synthesized ruthenium complexes with a bioactive molecule, the purine analogue 5,6,7-trimethyl-1,2,4-triazolo[1,5-a]pyrimidine (tmtp): cis,fac-[RuCl2(dmso)3(tmtp)] (1), mer-[RuCl3(dmso)(H2O)(tmtp)]·2H2O (2) and fac,cis-[RuCl3(H2O)(tmtp)2] (3). Their structures were characterized using X-ray and spectroscopic methods (IR, NMR or EPR). The stability of the synthesized complexes 1-3 in various buffered solutions (pH=3-7.4) was monitored using conventional and stopped-flow techniques. The in vitro antiproliferative activity of all ruthenium complexes against promastigote forms of Leishmania spp. (L. infantum, L. braziliensis, and L. donovani) and epimastigote forms of Trypanosoma cruzi was investigated. Notably, the results showed that the activity of 1 against L. brasiliensis was more than three-fold higher than that of glucantime, and 1 showed no appreciable toxicity towards J774.2 macrophages. Additionally, 2 displayed even 141-fold lower toxicity against host cells than glucantime, demonstrating significantly higher selectivity than the reference drug. Therefore, 1 and 2 appear to be excellent candidates for further development as potential drugs for the effective treatment of leishmaniasis and Chagas disease. All novel complexes were also shown to be potent inhibitors of Fe-SOD in the studied species, while their effects on human CuZn-SOD were very low.
Asunto(s)
Antiprotozoarios , Enfermedad de Chagas/tratamiento farmacológico , Complejos de Coordinación , Leishmania/metabolismo , Leishmaniasis/tratamiento farmacológico , Purinas , Rutenio , Trypanosoma cruzi/metabolismo , Animales , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Antiprotozoarios/farmacología , Enfermedad de Chagas/metabolismo , Chlorocebus aethiops , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Leishmaniasis/metabolismo , Ratones , Purinas/síntesis química , Purinas/química , Purinas/farmacología , Rutenio/química , Rutenio/farmacología , Células VeroRESUMEN
Six novel platinum(II) complexes containing purine-mimetic ligands (5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp), 7-isobutyl-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp)) and dicarboxylato ligands (glutarato (glut) or cyclobutane-1,1-dicarboxylato (CBDC)) have been prepared and characterized with multinuclear magnetic resonance (1H, 13C, 15N, 195Pt) NMR, infrared (IR) and X-ray crystallography. Spectroscopic data in solid state and in solution unambiguously confirm the square-planar geometry of Pt(II) with two monodentate N3-bonded 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidine ligands and one O-chelating dicarboxylato ligand. Next, the effect of all the platinum(II) compounds on the viability of normal or cancer cells and their putative mechanisms of action have been investigated. Of the studied platinum(II) complexes, two ([Pt(glut)(dbtp)2] and [Pt(CBDC)(dbtp)2]) overcame the cisplatin resistance in human ovarian tumor cells (A2780cis or OVCAR-3) and arrested the cell cycle at S phase in mice mammary gland cancer cells (4T1), which indicates a mechanism of action different from that of cisplatin. Interestingly, preliminary in vivo toxicity assays revealed that both compounds tested in mice ([Pt(glut)(dbtp)2] 3 and [Pt(CBDC)(dbtp)2] 6) were less toxic in vivo than cisplatin or oxaliplatin. Additionally, compound 6 did not cause myelosuppression and showed over fivefold less accumulation in the liver than its glutarato analog 3.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Diseño de Fármacos , Platino (Metal)/química , Purinas/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Biomimética , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/toxicidad , Femenino , Concentración 50 Inhibidora , Cinética , Ligandos , Ratones , Purinas/farmacologíaRESUMEN
New chiral camphane-derived benzisoselenazol-3(2H)-ones and corresponding diselenides have been synthetized using a convenient one-pot procedure. Se-N bond was efficiently converted to an Se-Se bond, which could also be easily re-oxidized to the initial benzisoselenazolone moiety. The antioxidant activity of camphor derivatives was evaluated and compared to the reactivity of a series of N-amino acid benzisoselenazol-3(2H)-ones obtained by a modified procedure involving the improved synthesis and isolation of the diseleno bis(dibenzoic) acid. The most efficient peroxide scavengers, N-bornyl and N-leucine methyl ester benzisoselenazol-3(2H)-ones, were further evaluated as cytotoxic agents on four cancer cell lines (MCF-7, HEP G2, HL 6, and DU 145) and normal cell line PNT1A. The highest antiproliferative potential was evaluated for two compounds bearing a 3-methylbutyl carbon chain, N-leucine methyl ester and N-3-methylbutyl benzisoselenazol-3(2H)-ones.
Asunto(s)
Antineoplásicos/síntesis química , Antioxidantes/síntesis química , Compuestos de Organoselenio/síntesis química , Tiazoles/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Azoles/química , Catálisis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Isoindoles , Células MCF-7 , Estructura Molecular , Compuestos Orgánicos , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Adenine nucleotides and adenosine are signaling molecules that activate purinergic receptors P1 and P2. Activation of A1 adenosine receptors has an anticonvulsant action, whereas activation of A2A receptors might initiate seizures. Therefore, a significant limitation to the use of A1 receptor agonists as drugs in the CNS might be their peripheral side effects. The anti-epileptic activity of adenosine is related to its increased concentration outside the cell. This increase might result from the inhibition of the equilibrative nucleoside transporters (ENTs). Moreover, the implantation of implants or stem cells into the brain might cause slow and persistent increases in adenosine concentrations in the extracellular spaces of the brain. The role of adenosine in seizure inhibition has been confirmed by results demonstrating that in patients with epilepsy, the adenosine kinase (ADK) present in astrocytes is the only purine-metabolizing enzyme that exhibits increased expression. Increased ADK activity causes intensified phosphorylation of adenosine to 5'-AMP, which therefore lowers the adenosine level in the extracellular spaces. These changes might initiate astrogliosis and epileptogenesis, which are the manifestations of epilepsy. Seizures might induce inflammatory processes and vice versa. Activation of P2X7 receptors causes intensified release of pro-inflammatory cytokines (IL-1ß and TNF-α) and activates metabolic pathways that induce inflammatory processes in the CNS. Therefore, antagonists of P2X7 and the interleukin 1ß receptor might be efficient drugs for recurring seizures and prolonged status epilepticus. Inhibitors of ADK would simultaneously inhibit the seizures, prevent the astrogliosis and epileptogenesis processes and prevent the formation of new epileptogenic foci. Therefore, these drugs might become beneficial seizure-suppressing drugs.