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1.
RSC Med Chem ; 14(5): 869-879, 2023 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-37252094

RESUMEN

Four coumarin-triazole hybrids were selected from our in house library and screened for cytotoxic activity on A549 (lung cancer), HepG2 (liver cancer), J774A1 (mouse sarcoma macrophage), MCF7 (breast cancer), OVACAR (ovarian cancer), RAW (murine leukaemia macrophage), and SiHa (uterus carcinoma) and their in vitro toxicity was assessed on 3T3 (healthy fibroblasts) cell lines. SwissADME pharmacokinetic prediction was performed. Effects on ROS production, mitochondrial membrane potential, apoptosis/necrosis and DNA damage were evaluated. All of the hybrids have good pharmacokinetic predictions. Each of them showed cytotoxic activity against the MCF7 breast cancer cell line, with IC50 between 2.66 and 10.08 µM, lower than cisplatin (45.33 µM) for the same test. One can observe an order of reactivity from the most potent: LaSOM 186 > LaSOM 190 > LaSOM 185 > LaSOM 180, with a better selectivity index than the reference drug cisplatin and the precursor hymecromone, and caused cell death by apoptosis induction. Two compounds showed antioxidant activity in vitro and three disrupted the mitochondrial membrane potential. None of the hybrids caused genotoxic damage to healthy 3T3 cells. All hybrids showed potential for further optimization, mechanism elucidation, in vivo activity and toxicity tests.

2.
Curr Med Chem ; 30(6): 689-700, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-35209817

RESUMEN

BACKGROUND: Alzheimer's disease (AD) is one of the most prevalent types of dementia, affecting millions of older people worldwide. AD is stimulating efforts to develop novel molecules targeting its main features associated with a decrease in acetylcholine levels, an increase in oxidative stress and depositions of amyloid-ß (Aß) and tau protein. In this regard, selenium-containing compounds have been demonstrated as potential multi-targeted compounds in the treatment of AD. These compounds are known for their antioxidant and anticholinesterase properties, causing a decrease in Aß aggregation. OBJECTIVE: In this review, we approach structure-activity relationships of each compound, associating the decrease of ROS activity, an increase of tau-like activity and inhibition of AChE with a decrease in the self-aggregation of Aß. METHODS: We also verify that the molecular descriptors apol, nHBAcc and MlogP may be related to optimized pharmacokinetic properties for anti-AD drugs. RESULTS: In our analysis, few selenium-derived compounds presented similar molecular features to FDA-approved drugs. CONCLUSION: We suggest that unknown selenium-derived molecules with apol, nHBAcc and MlogP like FDA-approved drugs may be better successes with optimized pharmacokinetic properties in future studies in AD.


Asunto(s)
Enfermedad de Alzheimer , Compuestos de Selenio , Selenio , Humanos , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Selenio/uso terapéutico , Compuestos de Selenio/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Estrés Oxidativo
3.
Neurotox Res ; 40(1): 127-139, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35043379

RESUMEN

Methylmercury (MeHg) is a ubiquitous environmental neurotoxicant whose mechanisms of action involve oxidation of endogenous nucleophilic groups (mainly thiols and selenols), depletion of antioxidant defenses, and disruption of neurotransmitter homeostasis. Diphenyl diselenide-(PhSe)2-a model diaryl diselenide, has been reported to display significant protective effects against MeHg-induced neurotoxicity under both in vitro and in vivo experimental conditions. In this study, we compared the protective effects of (PhSe)2 with those of RC513 (4,4'-diselanediylbis(2,6-di-tert-butylphenol), a novel diselenide-probucol-analog) against MeHg-induced toxicity in the neuronal (hippocampal) cell line HT22. Although both (PhSe)2 and RC513 significantly mitigated MeHg- and tert-butylhydroperoxide (t-BuOOH)-cytotoxicity, the probucol analog exhibited superior protective effects, which were observed earlier and at lower concentrations compared to (PhSe)2. RC513 treatment (at either 0.5 µM or 2 µM) significantly increased glutathione peroxidase (GPx) activity, which has been reported to counteract MeHg-toxicity. (PhSe)2 was also able to increase GPx activity, but only at 2 µM. Although both compounds increased the Gpx1 transcripts at 6 h after treatments, only RC513 was able to increase mRNA levels of Prx2, Prx3, Prx5, and Txn2, which are also involved in peroxide detoxification. RC513 (at 2 µM) significantly increased GPx-1 protein expression in HT22 cells, although (PhSe)2 displayed a minor (nonsignificant) effect in this parameter. In agreement, RC513 induced a faster and superior capability to cope with exogenously-added peroxide (t-BuOOH). In summary, when compared to the prototypical organic diaryl diselenide [(PhSe)2], RC513 displayed superior protective properties against MeHg-toxicity in vitro; this was paralleled by a more pronounced upregulation of defenses related to detoxification of peroxides, which are well-known MeHg-derived intermediate oxidant species.


Asunto(s)
Compuestos de Metilmercurio , Compuestos de Organoselenio , Derivados del Benceno/farmacología , Compuestos de Metilmercurio/toxicidad , Compuestos de Organoselenio/farmacología , Peróxidos , Probucol/farmacología
4.
Molecules ; 26(15)2021 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-34361597

RESUMEN

Herein, we describe a simple and efficient route to access aniline-derived diselenides and evaluate their antioxidant/GPx-mimetic properties. The diselenides were obtained in good yields via ipso-substitution/reduction from the readily available 2-nitroaromatic halides (Cl, Br, I). These diselenides present GPx-mimetic properties, showing better antioxidant activity than the standard GPx-mimetic compounds, ebselen and diphenyl diselenide. DFT analysis demonstrated that the electronic properties of the substituents determine the charge delocalization and the partial charge on selenium, which correlate with the catalytic performances. The amino group concurs in the stabilization of the selenolate intermediate through a hydrogen bond with the selenium.

5.
Eur J Med Chem ; 155: 503-515, 2018 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-29908443

RESUMEN

Novel pyrimidinic selenoureas were synthesized and evaluated against tumour and normal cell lines. Among these, the compound named 3j initially showed relevant cytotoxicity and selectivity for tumour cells. Three analogues of 3j were designed and synthesized keeping in view the structural requirements of this compound. Almost all the tested compounds displayed considerable cytotoxicity. However, 8a, one of the 3j analogues, was shown to be highly selective and cytotoxic, especially for breast carcinoma cells (MCF-7) (IC50 = 3.9 µM). Furthermore, 8a caused DNA damage, inhibited cell proliferation, was able to arrest cell cycle in S phase, and induced cell death by apoptosis in human breast carcinoma cells. Moreover, predictions of pharmacokinetic properties showed that 8a may present good absorption and permeation characteristics for oral administration. Overall, the current study established 8a as a potential drug prototype to be employed as a DNA interactive cytotoxic agent for the treatment of breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Compuestos de Organoselenio/farmacología , Pirimidinas/farmacología , Urea/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Daño del ADN , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HeLa , Humanos , Células MCF-7 , Estructura Molecular , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Células Tumorales Cultivadas , Urea/síntesis química , Urea/química , Urea/farmacología
6.
Bioorg Med Chem ; 24(22): 5762-5770, 2016 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-27681239

RESUMEN

This paper describes the synthesis and evaluation of new dihydropyrimidinone (DHPM)-derived selenoesters as potential multi-targeted agents for the treatment of Alzheimer's disease. A series of DHPM-derived selenoesters were obtained with high structural diversity through a short and modular synthetic route. The antioxidant activity was evaluated by TBARS and iron chelation assays. These compounds were also evaluated as acetylcholinesterase inhibitors (AChEi). The compounds demonstrated good antioxidant activity, since they presented excellent lipid peroxidation inhibition and good iron chelation activity. In addition, they showed acetylcholinesterase inhibition activity and some of them presented activity superior to that of the standard drug galantamine. The in silico predictions showed that the compound 1h may present a good pharmacokinetic profile. Therefore, the series of DHPM-derived selenoesters described herein displayed good potential for the development of antioxidant and anticholinesterasic agents in the search for new multi-targeted therapeutics for the treatment of Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antioxidantes/farmacología , Inhibidores de la Colinesterasa/farmacología , Ésteres/farmacología , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/farmacología , Pirimidinonas/farmacología , Enfermedad de Alzheimer/enzimología , Antioxidantes/síntesis química , Antioxidantes/química , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Ésteres/síntesis química , Ésteres/química , Humanos , Estructura Molecular , Compuestos de Organoselenio/química , Pirimidinonas/química , Relación Estructura-Actividad
7.
Eur J Med Chem ; 87: 131-9, 2014 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-25244678

RESUMEN

The antioxidant properties of organoselenium compounds have been extensively investigated with the aim of developing new drugs, since oxidative stress is responsible for a variety of chronic human diseases. Herein, we reported the synthesis of new nitrogen-containing diselenides by a simple and efficient synthetic route. The products were obtained in good to excellent yields and their identification and characterization were achieved by NMR and HRMS techniques. The new derivatives may represent promising structures with different biological activities, which can act against oxidative stress through diverse mechanisms of action. The glutathione peroxidase-like assay (GPx-like activity) of the new synthesized compounds indicated that they reduced H2O2 to water at the expense of PhSH. The best results were obtained with diselenide 2b, which was 9 times more active than the standard organoselenium drug ebselen and, in contrast, this compound was not reduced by hepatic TrxR. All of the new compounds inhibited Fe(II)-induced TBARS.


Asunto(s)
Antioxidantes/síntesis química , Antioxidantes/farmacología , Glutatión Peroxidasa/metabolismo , Nitrógeno/química , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/farmacología , Azoles/farmacología , Encéfalo/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/metabolismo , Isoindoles , Peroxidación de Lípido/efectos de los fármacos , Hígado/enzimología , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/química , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Tiorredoxina Reductasa 1/metabolismo
8.
Org Biomol Chem ; 12(21): 3470-7, 2014 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-24752799

RESUMEN

In this paper we report the design, synthesis and evaluation of a series of seleno-dihydropyrimidinones as potential multi-targeted therapeutics for Alzheimer's disease. The compounds show excellent results as acetylcholinesterase inhibitors, being as active as the standard drug. All these compounds also show very good antioxidant activity through different mechanisms of action.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Diseño de Fármacos , Terapia Molecular Dirigida , Pirimidinonas/síntesis química , Pirimidinonas/uso terapéutico , Selenio/uso terapéutico , Antioxidantes/farmacología , Inhibidores de la Colinesterasa/farmacología , Humanos , Pirimidinonas/química , Pirimidinonas/farmacocinética
9.
Xenobiotica ; 44(3): 254-63, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23937080

RESUMEN

1. The present work investigated the pharmacokinetic and tissue distribution as well as acute toxicity of a new chemical entity (NCE), the anticancer candidate LaSOM 65 in Wistar rats. 2. LaSOM 65 pharmacokinetics was investigated after intravenous (i.v., 1 mg/kg) and oral (p.o., 10 and 30 mg/kg) dosing. Tissue distribution was assessed after i.v. bolus dose. Acute toxicity was evaluated after i.v. (1, 2.5 and 5 mg/kg) and p.o. (50, 100 and 150 mg/kg) administration. 3. Short half-life (1.75 ± 0.71 h), a clearance of 0.85 ± 0.18 L/h/kg and a volume of distribution of 1.76 ± 0.24 L/kg were observed after i.v. dosing. The compound showed good bioavailability and linear pharmacokinetics after oral doses. The NCE distributes consistently in lung and fatty tissues, with penetration ratios of 2.7 and 1.4, respectively. The other tissues investigated presented smaller penetration ratios. Adverse clinical symptoms were observed only after i.v. administration, and regressed 3 h after dosing. Compared with controls, no statistical differences were found for serum analysis, body weight and relative organ weight, indicating no acute toxicological effects. 4. Overall, LaSOM 65 showed good pharmacokinetic characteristics and no signs of acute toxicity, indicating that it is a promising anticancer candidate.


Asunto(s)
Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Pirimidinas/farmacocinética , Pirimidinas/toxicidad , Tionas/farmacocinética , Tionas/toxicidad , Tejido Adiposo/metabolismo , Administración Intravenosa , Administración Oral , Análisis de Varianza , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Disponibilidad Biológica , Evaluación Preclínica de Medicamentos , Semivida , Pulmón/metabolismo , Masculino , Estructura Molecular , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Ratas Wistar , Tionas/administración & dosificación , Tionas/química , Distribución Tisular , Pruebas de Toxicidad Aguda
10.
Mem. Inst. Oswaldo Cruz ; 103(8): 773-777, Dec. 2008. ilus, tab
Artículo en Inglés | LILACS | ID: lil-502296

RESUMEN

A series of seven limonene β-amino alcohol derivatives has been regioselectively synthesised in moderate to good yields. Two of these compounds were found to be significantly effective against in vitro cultures of the Leishmania (Viannia) braziliensis promastigote form in the micromolar range. The activities found for 3b and 3f were about 100-fold more potent than the standard drug, Pentamidine, in the same test, while limonene did not display any activity. This is the first report of antileishmanial activity by limonene β-amino alcohol derivatives.


Asunto(s)
Animales , Ratones , Amino Alcoholes/síntesis química , Antiprotozoarios/síntesis química , Ciclohexenos/química , Leishmania braziliensis/efectos de los fármacos , Terpenos/química , Amino Alcoholes/farmacología , Amino Alcoholes/toxicidad , Antiprotozoarios/farmacología , Antiprotozoarios/toxicidad , Ciclohexenos/farmacología , Ciclohexenos/toxicidad , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Terpenos/farmacología , Terpenos/toxicidad
11.
Mem Inst Oswaldo Cruz ; 103(8): 773-7, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19148415

RESUMEN

A series of seven limonene beta-amino alcohol derivatives has been regioselectively synthesised in moderate to good yields. Two of these compounds were found to be significantly effective against in vitro cultures of the Leishmania (Viannia) braziliensis promastigote form in the micromolar range. The activities found for 3b and 3f were about 100-fold more potent than the standard drug, Pentamidine, in the same test, while limonene did not display any activity. This is the first report of antileishmanial activity by limonene beta-amino alcohol derivatives.


Asunto(s)
Amino Alcoholes/síntesis química , Antiprotozoarios/síntesis química , Ciclohexenos/química , Leishmania braziliensis/efectos de los fármacos , Terpenos/química , Amino Alcoholes/farmacología , Amino Alcoholes/toxicidad , Animales , Antiprotozoarios/farmacología , Antiprotozoarios/toxicidad , Ciclohexenos/farmacología , Ciclohexenos/toxicidad , Limoneno , Ratones , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Terpenos/farmacología , Terpenos/toxicidad
12.
Bioorg Chem ; 34(4): 173-82, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16765411

RESUMEN

The synthesis and differential antiproliferative activity of monastrol (1a), oxo-monastrol (1b) and eight oxygenated derivatives 3a,b-6a,b on seven human cancer cell lines are described. For all evaluated cell lines, monastrol (1a) was shown to be more active than its oxo-analogue, except for HT-29 cell line, suggesting the importance of the sulfur atom for the antiproliferative activity. Monastrol (1a) and the thio-derivatives 3a, 4a and 6a displayed relevant antiproliferative properties with 3,4-methylenedioxy derivative 6a being approximately more than 30 times more potent than monastrol (1a) against colon cancer (HT-29) cell line.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Oxígeno/química , Pirimidinas/síntesis química , Pirimidinas/farmacología , Tionas/síntesis química , Tionas/farmacología , Antineoplásicos/química , Línea Celular , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pirimidinas/química , Tionas/química
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