RESUMO
Stromal keratitis resulting from ocular infection with Herpes simplex virus type 1 (HSV-1) is a common cause of blindness. This report investigates the antiviral and anti-inflammatory properties of two new synthetic stigmastane analogs in the experimental model of HSV-1-induced ocular disease in mice. (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (1) and (22S,23S)-22,23-dihydroxystigmasta-1,4-dien-3-one (2) exhibited anti-HSV-1 activity in vitro and ameliorated the signs of murine herpetic stromal keratitis (HSK), although none of the compounds showed antiviral activity in vivo. We discuss that the improvement of HSK could be due to an immunomodulatory effect of both compounds.
Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Estigmasterol/análogos & derivados , Estigmasterol/síntese química , Animais , Antivirais/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Epitélio Corneano/efeitos dos fármacos , Epitélio Corneano/metabolismo , Formazans/metabolismo , Herpesvirus Humano 1/metabolismo , Humanos , Concentração Inibidora 50 , Ceratite Herpética/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Espectrofotometria , Sais de Tetrazólio/metabolismo , Fatores de Tempo , Células Vero , beta-Galactosidase/metabolismoRESUMO
In this paper, we report the synthesis and bioactivity of four synthetic analogues of 28-homobrassinosteroids, in order to evaluate the influence in bioactivity when the C-6 keto group is replaced by different functional groups. The synthetic analogues are 6-deoxo-28-homocastasterone [(22R,23R)-stigmasta-2alpha,3alpha,22,23-tetraol], 6alpha-hydroxy-28-homocastasterone [(22R,23R)-stigmasta-2alpha,3alpha,6alpha,22,23-pentaol], 6beta-hydroxy-28-homocastasterone [(22R,23R)-stigmasta-2alpha,3alpha,6beta,22,23-pentaol], and [(22R,23R)-6alpha-fluorostigmasta-2alpha,3alpha,22,23-tetraol]. Results indicate that replacement of the 6-keto moiety by an beta or alpha hydroxyl group led to a decrease in activity, whereas the 6-deoxo analogue showed a very low activity, confirming the importance of an electronegative moiety at C-6 to observe hormonal potency. The 6alpha-fluorinated analogue elicited a low activity, similar to that of the 6-deoxo analogue.
Assuntos
Colestanonas/química , Oryza/fisiologia , Reguladores de Crescimento de Plantas/química , Estigmasterol/análogos & derivados , Colestanonas/síntese química , Colestanonas/isolamento & purificação , Modelos Moleculares , Conformação Molecular , Reguladores de Crescimento de Plantas/síntese química , Reguladores de Crescimento de Plantas/isolamento & purificação , Plântula/fisiologia , Estigmasterol/síntese química , Estigmasterol/química , Estigmasterol/isolamento & purificaçãoRESUMO
Brassinosteroids are a novel group of steroids that appear to be ubiquitous in plants and are essential for normal plant growth and development. It has been previously reported that brassinosteroid analogues exert an antiviral activity against herpes simplex virus type 1 (HSV-1) and arenaviruses. In the present study, we report the chemical synthesis of compounds (22S,23S)-3beta-bromo-5alpha,22,23-trihydroxystigmastan-6-one (2), (22S,23S)-5alpha-fluoro-3beta-22,23-trihydroxystigmastan-6-one (3), (22S,23S)-3beta,5alpha,22,23-tetrahydroxy-stigmastan-6-one (4) as well as their antiherpetic activity both in a human conjunctive cell line (IOBA-NHC) and in the murine herpetic stromal keratitis (HSK) experimental model. All compounds prevented HSV-1 multiplication in NHC cells in a dose dependent manner when added after infection with no cytotoxicity. Administration of compounds 2, 3, and 4 to the eyes of mice at 1, 2, and 3 days post-infection delayed and reduced the incidence of HSK, consisting mainly of inflammation, vascularization, and necrosis, compared to untreated, infected mice. However, viral titers of eye washes showed no differences among samples from treated and untreated mice. Since the decrease in the percentage of mice with ocular lesions occurred 5 days after treatment had ended, we suggest that brassinosteroids 2, 3, and 4 did not exert a direct antiviral effect in vivo, but rather may play a role in immune-mediated stromal inflammation, which would explain the improvement of the clinical signs of HSK observed.
Assuntos
Antivirais/química , Antivirais/síntese química , Antivirais/farmacologia , Colestanonas/síntese química , Estigmasterol/análogos & derivados , Estigmasterol/síntese química , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Sobrevivência Celular , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Herpesvirus Humano 1/metabolismo , Humanos , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Químicos , Espectrofotometria , Esteroides/síntese química , Esteroides/química , Fatores de Tempo , Células Vero , beta-Galactosidase/metabolismoRESUMO
Assay-guided fractionation of an antitubercular extract obtained from Lessonia nigrescens yielded the phytosterol saringosterol as its active component. No appreciable toxicity against Vero cells was observed for this compound. Saringosterol was also synthesized by oxidation of fucosterol. The MIC values for antitubercular activity of saringosterol and its 24S and 24R epimers were determined as 0.25, 1, and 0.125 microg/mL.