RESUMO
The guanidine function in the potent neuraminidase inhibitor peramivir was included early on in the drug design process, and examination of X-ray structural data for the enzyme-inhibitor complex would seem to indicate that the guanidine plays a critical role in promoting binding. However, this functional group may also contribute to the poor oral availability of the drug. Given that the relative stereochemistry on the guanidine-bearing carbon in peramivir is opposite to that in zanamivir (a related neuraminidase inhibitor, for which the guanidine function is known to contribute substantially to the potency), we sought to determine the importance of the guanidine group to peramivir's overall potency. Here we report that the de-guanidinylated analogue of peramivir is only ca. 1-order of magnitude less potent than peramivir itself in two in vitro inhibition assays. This suggests that next-generation inhibitors designed to improve on peramivir's properties might profitably dispense with the guanidine function.
Assuntos
Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Desenho de Fármacos , Guanidinas/síntese química , Guanidinas/farmacologia , Vírus da Influenza A , Neuraminidase/antagonistas & inibidores , Ácidos Carbocíclicos , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Cristalografia por Raios X , Ciclopentanos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Guanidinas/química , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/enzimologia , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Neuraminidase/genética , Ligação Proteica , Proteínas Recombinantes/genética , Zanamivir/química , Zanamivir/farmacologiaRESUMO
Triclosan (TCS) and triclocarban (TCC) are widely used broad spectrum bactericides that are common pollutants of waterways and soils. Methyl triclosan (mTCS) is the predominant bacterial TCS metabolite. Previous studies have shown that TCS disrupts thyroid hormone (TH) action; however, the effects of mTCS or TCC are not known. The present study uses the cultured frog tadpole tail fin biopsy (C-fin) assay and the TH-responsive rat pituitary GH3 cell line to assess the effects of these three chemicals (1-1000 nM) on TH signaling and cellular stress within 48 h. mRNA abundance of TH receptor ß, Rana larval keratin type I (TH-response), heat shock protein 30, and catalase (stress-response) was measured using quantitative real-time polymerase chain reaction in the C-fin assay. The TH-responsive gene transcripts encoding growth hormone, deiodinase I, and prolactin were measured in GH3 cells with the heat shock protein 70 transcript acting as a cellular stress indicator. We found alteration of stress indicators at a wide range of concentrations of TCS, mTCS, and TCC in both test systems. mTCS and TCC affected TH-responsive gene transcripts at the highest concentration in mammalian cells, whereas a modest effect included lower concentrations in the C-fin assay. In contrast, TCS did not affect TH-responsive transcripts. These results identify nontarget biological effects of these bacteriocides on amphibian and mammalian cells and suggest the TH-disrupting effects observed for TCS could be mediated through its metabolite.
Assuntos
Carbanilidas/toxicidade , Mamíferos/fisiologia , Ranidae/fisiologia , Estresse Fisiológico/efeitos dos fármacos , Hormônios Tireóideos/farmacologia , Triclosan/análogos & derivados , Animais , Catalase/genética , Catalase/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Proteínas de Choque Térmico HSP30/genética , Proteínas de Choque Térmico HSP30/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Queratinas/genética , Queratinas/metabolismo , Larva/efeitos dos fármacos , Larva/genética , Técnicas de Cultura de Órgãos , Reação em Cadeia da Polimerase , Prolactina/genética , Prolactina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ranidae/genética , Ratos , Receptores beta dos Hormônios Tireóideos/efeitos dos fármacos , Receptores beta dos Hormônios Tireóideos/metabolismo , Triclosan/toxicidadeRESUMO
Here we present a transition metal-free synthesis of a rigid, orthogonally functionalized bicyclic sulfone, starting from readily available reagents. The transformation proceeds via a tandem vinylogous 1,2-addition/anionic oxy-Cope sequence, followed by a second vinylogous ketone addition. Stereochemical assignments suggest that the anionic oxy-Cope reaction proceeds exclusively through a boat-shaped transition state. The product of the two-step sequence can be further functionalized through subsequent chemo- and diastereoselective transformations, suggesting possible applications in medicinal chemistry or materials chemistry.
