RESUMO
There is growing interest in exploring Digitalis cardenolides as potential antiviral agents. Hence, we herein investigated the influence of structural features and lipophilicity on the antiherpes activity of 65 natural and semisynthetic cardenolides assayed inâ vitro against HSV-1. The presence of an α,ß-unsaturated lactone ring at C-17, a ß-hydroxy group at C-14 and C-3ß-OR substituents were considered essential requirements for this biological activity. Glycosides were more active than their genins, especially monoglycosides containing a rhamnose residue. The activity enhanced in derivatives bearing an aldehyde group at C-19 instead of a methyl group, whereas inserting a C-5ß-OH improved the antiherpes effect significantly. The cardenolides lipophilicity was accessed by measuring experimentally their log P values (n-octanol-water partition coefficient) and disclosed a range of lipophilicity (log P 0.75±0.25) associated with the optimal antiherpes activity. Inâ silico studies were carried out and resulted in the establishment of two predictive models potentially useful to identify and/or optimize novel antiherpes cardenolides. The effectiveness of the models was confirmed by retrospective analysis of the studied compounds. This is the first SAR study addressing the antiherpes activity of cardenolides. The developed computational models were able to predict the active cardenolides and their log P values.
Assuntos
Digitalis , Digitalis/química , Cardenolídeos/farmacologia , 1-Octanol , Ramnose , Estudos Retrospectivos , Extratos Vegetais/química , Antivirais/farmacologia , Glicosídeos , Lactonas , Aldeídos , ÁguaRESUMO
Digitalis purpurea L. is one of the main economically viable sources of cardenolides (cardiac glycosides) for the pharmaceutical industry. Nevertheless, production of cardenolides in plants grown by traditional agriculture is not always an efficient process and can be affected by biotic and abiotic factors. This chapter provides two biotechnology strategies for biomass and cardenolide production in D. purpurea. Firstly, we report biomass production using a temporary immersion system (TIS), combined with cardenolide extraction and quantification. Secondly, an efficient protocol for genetic transformation via Agrobacterium tumefaciens is provided. These strategies can be used independently or combined in order to increase the content of cardiac glycosides in D. purpurea and to unravel biosynthetic pathways associated to cardiac glycoside production.
Assuntos
Biotecnologia/métodos , Cardenolídeos/metabolismo , Digitalis/metabolismo , Agrobacterium tumefaciens/genética , Biomassa , Vias Biossintéticas , Biotecnologia/instrumentação , Cardenolídeos/análise , Cardenolídeos/isolamento & purificação , Técnicas de Cultura de Células/instrumentação , Técnicas de Cultura de Células/métodos , Digitalis/química , Digitalis/genética , Digitalis/microbiologia , Desenho de Equipamento , Transformação GenéticaRESUMO
Cardiac glycosides, known ligands of the sodium pump, are widely used in the treatment of heart failure, such as digoxin and digitoxin. Besides this important activity, other biological activities, such as the antiviral activity, have been described for this group. HSV are responsible for many infections of oral, ocular and genital regions. Treatment with nucleoside analogs such as acyclovir is effective in most cases; however drug-resistance may arise due to prolonged treatment mainly in immunocompromised individuals. In this study, an antiherpes screening was performed with 65 cardenolide derivatives obtained from different sources, and one natural cardenolide, glucoevatromonoside, inhibited HSV-1 and HSV-2 replication at very low concentrations. This cardenolide showed viral inhibitory effects if added up to 12h p.i. and these effects appear to take place by the inhibition of viral proteins synthesis (ICP27, U(L)42, gB, gD), the blockage of virus release and the reduction of viral cell-to-cell spread. This compound also showed synergistic antiviral effects with acyclovir and anti-Na(+)K(+)ATPase activity, suggesting that cellular electrochemical gradient alterations might be involved in the mechanism of viral inhibition. These results suggest that cardenolides might be promising for future antiviral drug design.
Assuntos
Antivirais/farmacologia , Cardenolídeos/farmacologia , Digitalis/química , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Extratos Vegetais/farmacologia , Antivirais/isolamento & purificação , Brasil , Cardenolídeos/isolamento & purificação , Linhagem Celular , Digitalis/crescimento & desenvolvimento , Avaliação Pré-Clínica de Medicamentos , Herpes Simples/tratamento farmacológico , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/fisiologia , Humanos , Extratos Vegetais/isolamento & purificação , Proteínas Virais/genética , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
Se presentan aspectos históricos, fitoquímicos, farmacológicos, toxicológicos y referentes a la utilidad medicinal de Digitalis spp., género con gran valor ornamental y comercial, sobre todo para elaborar purpureaglucósidos, digitoxina y gitoxina, compuestos utilizado en el tratamiento de enfermedades cardiacas. Digitalis purpurea fue utilizada desde el siglo XI y experimentada científicamente por W. Whitering en 1785, Inglaterra. Se le cultiva en Europa y en Estados Unidos de América del Norte, al igual que otras especies como Digitalis lanata Ehrh. y Digitalis lutea L.; actualmente son objeto de numerosos estudios y cultivos in vitro
Assuntos
Digitalis/química , Botânica , Glicosídeos Digitálicos/farmacologia , Glicosídeos Digitálicos/toxicidade , Plantas Medicinais , História da MedicinaRESUMO
Cardenolides from a Brazilian cultivar of Digitalis lanata were isolated by rotation locular countercurrent chromatography (RLCC), employing dichloromethane-methanol-water (5:6:4, v/v) as the solvent system. Highly pure lanatoside C was obtained from the Digitalis lanata hydromethanolic extract, pre-purified either by silica gel or reversed-phase chromatography.