RESUMO
Ruthenium compounds are known to be potential drug candidates since they offer the potential for reduced toxicity. Furthermore, the various oxidation states, different mechanisms of action and ligand substitution kinetics give them advantages over platinum-based complexes, making them suitable for use in biological applications. So, herein, novel ruthenium(II) complexes with metronidazole as ligand were obtained [RuCl(MTNZ)(dppb)(4,4'-Mebipy)]PF6 (1), [RuCl(MTNZ)(dppb)(4,4'-Methoxybipy)]PF6 (2), [RuCl(MTNZ)(dppb)(bipy)]PF6 (3) and [RuCl(MTNZ)(dppb)(phen)]PF6 (4) where, MTNZ = metronidazole, dppb = 1,4-bis(diphenylphosphino)butane, 4,4'-Mebipy = 4,4'-dimethyl-2,2'-bipyridine, 4,4'-Methoxybipy = 4,4'-dimethoxy-2,2'-bipyridine, bipy = 2,2'-bipyridine and phen = 1,10-phenanthroline. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-Vis spectroscopy, cyclic voltammetry, 31P{1H}, 1H, 13C{1H} and Dept 135 NMR and mass spectrometry. The interaction of complexes 1-4 with DNA was evaluated, and their cytotoxicity profiles were determined on four different tumor cell lines derived from human cancers (SK-MEL-147, melanoma; HepG2, hepatocarcinoma; MCF-7, estrogen-positive breast cancer; A549, non-small cell lung cancer). We demonstrated that complexes (1) and (3) are promising antitumor agents once inhibited the proliferative behavior of MCF-7 cells and induced apoptosis.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Complexos de Coordenação , Neoplasias Pulmonares , Rutênio , Humanos , Rutênio/química , Células MCF-7 , Metronidazol , 2,2'-Dipiridil/química , Complexos de Coordenação/química , Ligantes , Antineoplásicos/química , Linhagem Celular Tumoral , Pontos de Checagem do Ciclo Celular , ApoptoseRESUMO
In the present study, novel, 1,3-diaryltriazene-derived triazene compounds were synthesized and tested. Triazenes are versatile and belong to a group of alkylating agents with interesting physicochemical properties and proven biological activities. This study describes the synthesis, molecular and crystalline structure, biological activity evaluation, and antifungal and antimicrobial potentials of 1,3-bis(X-methoxy-Y-nitrophenyl)triazenes [X = 2 and 5; Y = 4 and 5]. The antimicrobial and antifungal activities of the compounds were tested by evaluating the sensitivity of bacteria (American Type Culture Collection, ATCC) and clinical isolates to their solutions using standardized microbiological assays, cytotoxicity evaluation, and ecotoxicity tests. The antimicrobial potentials of triazenes were determined according to their minimum inhibitory concentrations (MICs); these compounds were active against gram-positive and gram-negative bacteria, with low MIC values. The most surprising result was obtained for T3 having the effective MIC of 9.937 µg/mL and antifungal activity against Candida albicans ATCC 90028, C. parapsilosis ATCC 22019, and C. tropicallis IC. To the best of our knowledge, this study is the first to report promising activities of triazene compounds against yeast and filamentous fungi. The results showed the potential utility of triazenes as agents affecting selected resistant bacterial and fungal strains.
Assuntos
Triazenos/química , Triazenos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Leishmaniasis is a parasitic disease caused by protozoa of the genus Leishmania, which has very limited treatment options and affects poor and underdeveloped populations. The current treatment is plagued by many complications, such as high toxicity, high cost and resistance to parasites; therefore, novel therapeutic agents are urgently needed. Herein, the synthesis, characterization and in vitro leishmanicidal potential of new complexes with the general formula [RuCl3(TMP)(dppb)] (1), [PtCl(TMP)(PPh3)2]PF6 (2) and [Cu(CH3COO)2(TMP)2]·DMF (3) (dppb = 1,4-bis(diphenylphosphino)butane, PPH3 = triphenylphosphine and TMP = trimethoprim) were evaluated. The complexes were characterized by infrared, UV-vis, cyclic voltammetry, molar conductance measurements, elemental analysis and NMR experiments. Also, the geometry of (2) and (3) were determined by single crystal X-ray diffraction. Despite being less potent against promastigote L. amazonensis proliferation than amphotericin B reference drug (IC50 = 0.09 ± 0.02 µM), complex (2) (IC50 = 3.6 ± 1.5 µM) was several times less cytotoxic (CC50 = 17.8 µM, SI = 4.9) in comparison with amphotericin B (CC50 = 3.3 µM, SI = 36.6) and gentian violet control (CC50 = 0.8 µM). Additionally, complex (2) inhibited J774 macrophage infection and amastigote number by macrophages (IC50 = 6.6 and SI = 2.7). Outstandingly, complex (2) was shown to be a promising candidate for a new leishmanicidal therapeutic agent, considering its biological power combined with low toxicity.
Assuntos
Antiprotozoários , Complexos de Coordenação , Cobre , Leishmania/crescimento & desenvolvimento , Leishmaniose/tratamento farmacológico , Platina , Rubídio , Trimetoprima , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/farmacologia , Linhagem Celular , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Cobre/farmacologia , Cristalografia por Raios X , Leishmaniose/metabolismo , Leishmaniose/patologia , Camundongos , Estrutura Molecular , Platina/química , Platina/farmacologia , Rubídio/química , Rubídio/farmacologia , Trimetoprima/química , Trimetoprima/farmacologiaRESUMO
Research has shown that chitosan induces plant stress tolerance and protection, but few studies have explored chemical modifications of chitosan and their effects on plants under water stress. Chitosan and its derivatives were applied (isolated or in mixture) to maize hybrids sensitive to water deficit under greenhouse conditions through foliar spraying at the pre-flowering stage. After the application, water deficit was induced for 15 days. Analyses of leaves and biochemical gas exchange in the ear leaf were performed on the first and fifteenth days of the stress period. Production attributes were also analysed at the end of the experiment. In general, the application of the two chitosan derivatives or their mixture potentiated the activities of the antioxidant enzymes superoxide dismutase, catalase, ascorbate peroxidase, glutathione reductase and guaiacol peroxidase at the beginning of the stress period, in addition to reducing lipid peroxidation (malonaldehyde content) and increasing gas exchange and proline contents at the end of the stress period. The derivatives also increased the content of phenolic compounds and the activity of enzymes involved in their production (phenylalanine ammonia lyase and tyrosine ammonia lyase). Dehydroascorbate reductase and compounds such as total soluble sugars, total amino acids, starch, grain yield and harvest index increased for both the derivatives and chitosan. However, the mixture of derivatives was the treatment that led to the higher increase in grain yield and harvest index compared to the other treatments. The application of semisynthetic molecules derived from chitosan yielded greater leaf gas exchange and a higher incidence of the biochemical conditions that relieve plant stress.
Assuntos
Antioxidantes/metabolismo , Quitosana/farmacologia , Fotossíntese/efeitos dos fármacos , Zea mays/crescimento & desenvolvimento , Antioxidantes/química , Ascorbato Peroxidases/metabolismo , Catalase/genética , Catalase/metabolismo , Quitosana/síntese química , Grão Comestível/efeitos dos fármacos , Grão Comestível/crescimento & desenvolvimento , Glutationa Redutase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/metabolismo , Peroxidase/metabolismo , Folhas de Planta/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Água/química , Zea mays/efeitos dos fármacosRESUMO
Spironolactone (SPR) is a poorly water-soluble drug widely used for the treatment of various diseases. The objective of this study was to carry out the preparation and solid-state characterization of SPR 1/3 hydrate. The solid form was generated by an unreported recrystallization process in acetone and characterized for the first time by a combination of X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), equilibrium solubility, and an accelerated stability study. XRD, DSC, and TGA studies revealed that SPR 1/3 hydrated converts completely to form II after heating to 180°C. Solubility studies at 37°C showed that SPR 1/3 hydrate was statistically less soluble than SPR form II in all tested media and that SPR form II partially converts to SPR 1/3 hydrate in aqueous media. Accelerated stability studies demonstrated that both forms were physically and chemically stable up to 6 months (40°C/75% RH). We concluded that contamination of SPR 1/3 hydrate in SPR raw materials is undesirable. Taking this into account we recommend its polymorphic monitoring either in active pharmaceutical ingredients or commercial tablets by solid-state identification/quantification methods (XRD, DSC, TGA, and FTIR). Of these, XRD proved to be the most conclusive and accurate.
Assuntos
Espironolactona/química , Varredura Diferencial de Calorimetria/métodos , Cristalização/métodos , Pós/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Comprimidos/química , Água/química , Difração de Raios X/métodosRESUMO
Piplartine (piperlongumine) is a plant-derived compound found in some Piper species that became a novel potential antineoplastic agent. In the present study, we synthesized a novel platinum complex containing a piplartine derivative cis-[PtCl(PIP-OH)(PPh3)2]PF6 (where, PIP-OH = piplartine demethylated derivative; and PPh3 = triphenylphosphine) with enhanced cytotoxicity in different cancer cells, and investigated its apoptotic action in human promyelocytic leukemia HL-60 cells. The structure of PIP-OH ligand was characterized by X-ray crystallographic analysis and the resulting platinum complex was characterized by infrared, molar conductance measurements, elemental analysis and NMR experiments. We found that the complex is more potent than piplartine in a panel of cancer cell lines. Apoptotic cell morphology, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HL-60 cells. Treatment with the complex also caused a marked increase in the production of reactive oxygen species (ROS), and the pretreatment with N-acetyl-L-cysteine, an antioxidant, reduced the complex-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. Important, pretreatment with a p38 MAPK inhibitor (PD 169316) and MEK inhibitor (U-0126), known to inhibit ERK1/2 activation, also prevented the complex-induced apoptosis. The complex did not induce DNA intercalation in cell-free DNA assays. In conclusion, the complex exhibits more potent cytotoxicity than piplartine in a panel of different cancer cells and triggers ROS/ERK/p38-mediated apoptosis in HL-60 cells.
Assuntos
Apoptose/efeitos dos fármacos , Leucemia Promielocítica Aguda/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Platina/farmacologia , Caspases/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Ligantes , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Platina/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Glimepiride (GLIM) is used as an oral antihyperglycemic agent for treatment of type 2 diabetes. The drug presents two polymorphic forms (GLIM form I and GLIM form II) described in the literature, and according to in vitro data, GLIM form II is about 3.5 times more soluble and releases 2 times the drug amount than GLIM form I in the physiological pH range. Considering the literature in vitro data and that the diabetes treatment demands glycemic control, avoiding abrupt fluctuations in the blood glucose levels, this work aimed to study the impact of GLIM polymorphism in the in vivo performance of GLIM solid oral dosages. For this, hard gelatin capsules with GLIM form I or II were prepared and orally administered in rats. After that, pharmacokinetic studies were performed by sampling animal blood at different times, and biochemical parameters (pharmacodynamic), such as glucose and insulin, were also evaluated. Our results showed that the in vitro data corroborate with our in vivo assays. GLIM form II provided higher plasma concentration of drug than form I (at baseline up to approximately 200â¯min after oral administration) and, consequently, increased insulin release and reduced levels of glucose, showing good correlation between pharmacokinetic and pharmacodynamics assays. Thus, this study demonstrated that GLIM polymorphs in oral dosages might alter the drug efficacy, which may expose the patients to risks, such as hypoglycemia.
Assuntos
Glicemia/efeitos dos fármacos , Hipoglicemiantes/química , Insulina/sangue , Compostos de Sulfonilureia/química , Administração Oral , Animais , Cápsulas , Cristalização , Gelatina , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Ratos , Ratos Wistar , Solubilidade , Compostos de Sulfonilureia/farmacocinética , Compostos de Sulfonilureia/farmacologiaRESUMO
Herein, novel ruthenium(II) complexes containing 1-methylimidazole as a ligand were obtained with the following formulas: [RuCl(1Meim)(dppb)(bpy)]Cl (1), [RuCl(1Meim)(dppb)(4,4'-DMbpy)]Cl (2), [RuCl(1Meim)(dppb)(5,5'-DMbpy)]Cl (3) and [RuCl(1Meim)(dppb)(phen)]Cl (4) where, 1Meimâ¯=â¯1-methylimidazole, dppbâ¯=â¯1,4-Bis(diphenylphosphino)butane, bpyâ¯=â¯2,2'-bipyridine, 4,4'-DMbpyâ¯=â¯4,4'-dimethyl-2,2'-bipyridine, 5,5'-DMbpyâ¯=â¯5,5'-dimethyl-2,2'-bipyridine and phenâ¯=â¯1,10-phenanthroline. Additionally, crystal structures containing the cations of (1) and (3) were obtained when the counter ion was exchanged, leading to the formation of [RuCl(1Meim)(dppb)(bpy)]PF6 (5) and [RuCl(1Meim)(dppb)(5,5'-DMbpy)]PF6 methanol solvate (6) where PF6â¯=â¯hexafluorophosphate, showing one 1-methylimidazole molecule coordinated through the imidazole nitrogen, as expected. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-Vis spectroscopy, 1H, 13C{1H} and 31P{1H} NMR, mass spectrometry and cyclic voltammetry. The interactions of complexes 1-4 with DNA and human serum albumin (HSA) were evaluated, and the cytotoxicity profiles of compounds 1-4 were determined using four different tumor cell lines derived from human cancers (melanoma: HT-144, colon: HCT-8, breast: MDA-MB-231 and lung: A549). A higher cytotoxic activity was observed for compound (3) against non-small cell lung cancer (A549). Complex (3) inhibited the clonogenic capacity and cell cycle progression of A549 cells and induced apoptosis involving mitochondrial pathway activation. Therefore, the data obtained in the present study support further investigations concerning molecular targets of complex (3) in non-small cell lung cancer.
Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas , Complexos de Coordenação , Imidazóis , Rutênio , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Rutênio/química , Rutênio/farmacologiaRESUMO
ABSTRACT Different solid forms of an active pharmaceutical ingredient can have distinct chemical and physical characteristics. In this work, we studied the solubility and dissolution properties of the described tibolone polymorphic forms (I and II). Both forms were successively recrystallized and characterized by powder X-ray diffraction and attenuated total reflection infrared spectroscopy. Equilibrium solubility and dissolution profiles were performed for both forms. Solubility studies demonstrated that form II is statistically more soluble in water, 0.01 mol L-1 HCl and pH 4.5 acetate buffer. The solubility of forms I and II were explained in terms of crystal packing. Dissolution tests of tablets showed a lower release of polymorphic form II than form I from tablets. The results showed an impact of polymorphism on the quality of tibolone tablets and suggest that tibolone forms I and II can show distinct interactions with pharmaceutical excipients used in tablets. Therefore, only form I is acceptable for the preparation of tablet forms. Based on our results, we propose the quality control on tibolone raw materials using X-ray diffraction analysis and attenuated total reflection infrared spectroscopy.
Assuntos
Solubilidade/efeitos dos fármacos , Dissolução/análise , Análise Espectral , Comprimidos/normas , Difração de Raios X/métodos , Preparações Farmacêuticas/normasRESUMO
Orbifloxacin (ORBI) is a widely used antimicrobial drug of the fluoroquinolone class. In the official pharmaceutical compendia the existence of polymorphism in this active pharmaceutical ingredient (API) is reported. No crystal structure has been reported for this API and as described in the literature, its solubility is very controversial. Considering that different solid forms of the same API may have different physicochemical properties, these different solubilities may have resulted from analyses inadvertently carried out on different polymorphs. The solubility is the most critical property because it can affect the bioavailability and may compromise the quality of a drug product. The crystalline structure of ORBI determined by SCXRD is reported here for the first time. The structural analysis reveals that the ORBI molecule is zwitterionic and hemihydrated. ORBI hemihydrated form was characterized by the following techniques: TG/DTA, FTIR-ATR, and PXRD. A second crystalline ORBI form is also reported: the ORBI anhydrous form was obtained by heating the hemihydrate. These ORBI solid forms were isomorphous, since no significant change in unit cell and space group symmetry were observed. The solid-state phase transformation between these forms is discussed and the equilibrium solubility data were examined in order to check the impact of the differences observed in their crystalline structures.