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1.
J Biochem Mol Toxicol ; 37(7): e23356, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37009961

RESUMO

Zidovudine (AZT) is the most commonly prescribed antiviral drug for the treatment of human immunodeficiency virus (HIV) infection. However, its chronic administration causes toxic side effects limiting its use. This study aimed to evaluate the toxicity of different concentrations of AZT and novel chalcogen derivatives (7A, 7D, 7G, 7K, 7M) on locomotion, mitochondrial dysfunction, acetylcholinesterase (AChE) activity, and production of reactive oxygen species (ROS) in adult Drosophila melanogaster. Our results show that AZT and its derivative 7K at a concentration of 10 µM impaired flies' locomotor behavior. Furthermore, AZT and the derivatives 7K, 7A, and 7M induced mitochondrial dysfunction observed by a decrease in oxygen flux through mitochondrial complexes I and II. Neither of the compounds tested affected AChE activity or ROS production in flies. According to these data, AZT derivatives presented the following decreasing order of toxicity: 7K > AZT > 7G > 7A > 7M > 7D. Based on the chemical structure, it is possible to infer that the presence of the seleno-phenyl group in 7A and 7G increases their toxicity compared to compounds 7D and 7M. In addition, compounds 7G, 7M, and 7K with three carbon atoms as spacer were more toxic than analogs containing one carbon atom (7A and 7D). Finally, the insertion of a p-methoxyl group enhances toxicity (7K). Based on these results, excepting 7K, all other chalcogen derivatives presented lower toxicity than AZT and are potential drug candidates.


Assuntos
Fármacos Anti-HIV , Calcogênios , Animais , Humanos , Zidovudina/toxicidade , Drosophila melanogaster , Espécies Reativas de Oxigênio , Acetilcolinesterase , Fármacos Anti-HIV/toxicidade
2.
J Trace Elem Med Biol ; 50: 240-248, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30262286

RESUMO

INTRODUCTION: The incorporation of selenium in the structure of nucleosides is a promising strategy to develop novel therapeutic molecules. OBJECTIVE: To assess the toxic effects of three AZT derivatives containing organoselenium moieties on human erythrocytes. METHODOLOGY: Freshly human erythrocytes were acutely treated with AZT and selenium derivatives SZ1 (chlorophenylseleno), SZ2 (phenylseleno) and SZ3 (methylphenylseleno) at concentrations ranging from 10 to 500 µM. Afterwards, parameters related to membrane damage, redox dyshomeostasis and eryptosis were determined in the cells. RESULTS: The effects of AZT and derivatives toward erythrocytes differed considerably. Overall, the SZ3 exhibited similar effect profiles to the prototypal AZT, without causing cytotoxicity. Contrary, the derivative SZ1 induced hemolysis and increased the membrane fragility of cells. Reactive species generation, lipid peroxidation and thiol depletion were also substantially increased in cells after exposure to SZ1. δ-ALA-D and Na+/K+-ATPase activities were inhibited by derivatives SZ1 and SZ2. Additionally, both derivatives caused eryptosis, promoting cell shrinkage and translocation of phosphatidylserine at the membrane surface. The size and granularity of erythrocytes were not modified by any compound. CONCLUSION: The insertion of either chlorophenylseleno or, in a certain way, phenylseleno moietes in the structure of AZT molecule was harmful to erythrocytes and this effect seems to involve a pro-oxidant activity. This was not true for the derivative encompassing methylphenylseleno portion, making it a promising candidate for pharmacological studies.


Assuntos
Azidas/efeitos adversos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Selênio/metabolismo , Zidovudina/efeitos adversos , Azidas/química , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
3.
Chemistry ; 24(39): 9788-9793, 2018 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-29882608

RESUMO

Aiming at providing an efficient and versatile method for the diversity-oriented decoration and ligation of fullerenes, we report the first C60 derivatization strategy based on isocyanide-multicomponent reactions (I-MCRs). The approach comprises the use of Passerini and Ugi reactions for assembling pseudo-peptidic scaffolds (i.e., N-alkylated and depsipeptides, peptoids) on carboxylic acid-functionalized fullerenes. The method showed wide substrate scope for the oxo and isocyanide components, albeit the Ugi reaction proved efficient only for aromatic amines. The approach was successfully employed for the ligation of oligopeptides and polyethyleneglycol chains (PEG) to C60 , as well as for the construction of bis-antennary as well as PEG-tethered dimeric fullerenes. The quantum yields for the formation of 1 O2 was remarkable for the selected compounds analyzed.

4.
Toxicol Sci ; 160(1): 30-46, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29036705

RESUMO

Considering a novel series of zidovudine (AZT) derivatives encompassing selenoaryl moieties promising candidates as therapeutics, we examined the toxicities elicited by AZT and derivatives 5'-(4-Chlorophenylseleno)zidovudine (SZ1); 5'-(Phenylseleno)zidovudine (SZ2); and 5'-(4-Methylphenylseleno)zidovudine (SZ3) in healthy cells and in mice. Resting and stimulated cultured human peripheral blood mononuclear cells (PBMCs) were treated with the compounds at concentrations ranging from 10 to 200 µM for 24 and/or 72 h. Adult mice received a single injection of compounds (100 µmol/kg, s.c.) and 72 h after administration, hepatic/renal biomarkers were analyzed. Resting and stimulated PBMCs exposed to SZ1 displayed loss of viability, increased reactive species production, disruption in cell cycle, apoptosis and increased transcript levels and production of pro-inflammatory cytokines. In a mild way, most of these effects were also induced by SZ2. AZT and SZ3 did not cause significant toxicity towards resting PBMCs. Differently, both compounds elicited apoptosis and S phase arrest in stimulated cells. AZT and derivatives administration did not change the body weight and plasma biochemical markers in mice. However, the absolute weight and organ-to-body weight ratio of liver, kidneys and spleen were altered in AZT, SZ1-, and SZ2-treated mice. Our results highlighted the involvement of derivatives SZ1 and SZ2 in redox and immunological dyshomeostasis leading to activation of apoptotic signaling pathways in healthy cells under different division phases. On the other hand, the derivative SZ3 emerged as a promising candidate for further viral infection/antitumor studies as a new effective therapy with low toxicity for immune cells and after acute in vivo treatment.


Assuntos
Antineoplásicos/toxicidade , Calcogênios/toxicidade , Leucócitos Mononucleares/efeitos dos fármacos , Zidovudina/toxicidade , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Comportamento Animal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Medição de Risco , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Zidovudina/análogos & derivados
5.
J Med Chem ; 58(8): 3329-39, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25811955

RESUMO

In this article we present the synthesis, characterization, and in vitro biological and biochemical activities of new chalcogenozidovudine derivatives as antioxidant (inhibition of TBARS in brain membranes and thiol peroxidase-like activity) as well as antitumoral agents in bladder carcinoma 5637. A prominent response was obtained for the selected chalcogenonucleosides, showing effective antioxidant and antitumoral activities.


Assuntos
Antineoplásicos/química , Antioxidantes/química , Calcogênios/química , Neoplasias da Bexiga Urinária/tratamento farmacológico , Zidovudina/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Calcogênios/síntese química , Calcogênios/farmacologia , Humanos , Masculino , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Zidovudina/síntese química , Zidovudina/farmacologia
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