RESUMO
Halogenated bisphenol A (BPA) derivatives are produced during disinfection treatment of drinking water or are synthesized as flame retardants (TCBPA or TBBPA). BPA is considered as an endocrine disruptor especially on human follicle-stimulating hormone receptor (FSHR). Using a global experimental approach, we assessed the effect of halogenated BPA derivatives on FSHR activity and estimated the risk of halogenated BPA derivatives to the reproductive health of exposed populations. For the first time, we show that FSHR binds halogenated BPA derivatives, at 10 nM, a concentration lower than those requires to modulate the activity of nuclear receptors and/or steroidogenesis enzymes. Indeed, bioluminescence assays show that FSHR response is lowered up to 42.36 % in the presence of BPA, up to 32.79 % by chlorinated BPA derivatives and up to 27.04 % by brominated BPA derivatives, at non-cytotoxic concentrations and without modification of basal receptor activity. Moreover, molecular docking, molecular dynamics simulations, and site-directed mutagenesis experiments demonstrate that the halogenated BPA derivatives bind the FSHR transmembrane domain reducing the signal transduction efficiency which lowers the cellular cAMP production and in fine disrupts the physiological effect of FSH. The potential reproductive health risk of exposed individuals was estimated by comparing urinary concentrations (through a collection of human biomonitoring data) with the lowest effective concentrations derived from in vitro cell assays. Our results suggest a potentially high concern for the risk of inhibition of the FSHR pathway. This global approach based on FSHR activity could enable the rapid characterization of the toxicity of halogenated BPA derivatives (or other compounds) and assess the associated risk of exposure to these halogenated BPA derivatives.
Assuntos
Compostos Benzidrílicos , Disruptores Endócrinos , Simulação de Acoplamento Molecular , Fenóis , Receptores do FSH , Humanos , Fenóis/toxicidade , Fenóis/química , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/química , Receptores do FSH/metabolismo , Medição de Risco , Disruptores Endócrinos/toxicidade , Disruptores Endócrinos/química , Halogenação , Células HEK293 , Simulação de Dinâmica MolecularAssuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Receptores de Folato com Âncoras de GPI/metabolismo , beta-Galactosidase/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Ligantes , Neoplasias/tratamento farmacológicoAssuntos
Internação Compulsória de Doente Mental , Comportamento Perigoso , Hospitais Psiquiátricos , Transtornos Mentais/enfermagem , Equipe de Enfermagem , Equipe de Assistência ao Paciente , Auxiliares de Psiquiatria , Agressão/psicologia , Internação Compulsória de Doente Mental/legislação & jurisprudência , Comunicação , Comportamento Cooperativo , Intervenção em Crise/legislação & jurisprudência , França , Hospitais Psiquiátricos/legislação & jurisprudência , Humanos , Motivação , Equipe de Assistência ao Paciente/legislação & jurisprudênciaRESUMO
Two glucuronide prodrugs of the histone deacetylase inhibitor CI-994 were synthesized. These compounds were found to be soluble in aqueous media and stable under physiological conditions. The carbamoyl derivatisation of CI-994 significantly decreased its toxicity towards NCI-H661 lung cancer cells. Prodrug incubation with beta-glucuronidase in the culture media led efficiently to the release of the parent drug and thereby restoring its ability to decrease cell proliferation, to inhibit HDAC and to induce E-Cadherin expression.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores Enzimáticos/farmacologia , Glucuronídeos/farmacologia , Inibidores de Histona Desacetilases , Neoplasias Pulmonares/tratamento farmacológico , Fenilenodiaminas/farmacologia , Pró-Fármacos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/síntese química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Benzamidas , Caderinas/genética , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucuronídeos/síntese química , Glucuronídeos/química , Humanos , Hidrólise , Estrutura Molecular , Fenilenodiaminas/síntese química , Fenilenodiaminas/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de Tempo , Células Tumorais CultivadasRESUMO
The first O-glycosylation of hydroxamic acids is reported. This process involves the use of glycosyl N-phenyl trifluoroacetimidates as glycosyl donors in the presence TMSOTf and 4 A molecular sieves in dichloromethane. Under such conditions, a wide range of new glycosyl donors including glucosyl, galactosyl, mannosyl, glucuronyl, and ribosyl hydroxamates were prepared in good to high yields. This procedure appears to be an advantageous alternative for the synthesis of glycosyl hydroxamates of biological interest.
Assuntos
Fluoracetatos , Ácidos Hidroxâmicos/química , Acetamidas , Configuração de Carboidratos , Glicosilação , Estrutura Molecular , Ácido Trifluoracético/químicaRESUMO
The beta-O-glucuronide and beta-O-galactoside of SAHA have been prepared and evaluated as prodrugs for selective cancer chemotherapy (ADEPT, PMT). These new compounds are stable under physiological conditions and do not exhibit any antiproliferative activity compared to the parent drug after a 48-h treatment of H661 cells. The glucuronide derivative did not lead to the release of the drug in the presence of either Escherichia coli or bovine liver beta-glucuronidase. On the other hand, under enzymatic cleavage of galactoside prodrug by the corresponding enzyme, a rapid release of SAHA was observed demonstrating that the beta-O-galactoside of SAHA is a promising candidate for in vivo investigations.