RESUMO
The aim of the present study is to report the isolation, structural elucidation, and antiviral evaluation of four new withanolide-type steroids, named nicansteroidins A-D (1-4), together with nine related known compounds (5-13) isolated from the aerial parts of Physalis nicandroides. Their structures were established based on an extensive spectroscopic analysis, including 1D and 2D NMR techniques. Outstandingly, nicansteroidins A and B possess an unusual side chain with an exocyclic double bond on the δ-lactone system, whereas nicansteroidins C and D have an uncommon cycloperoxide functionality in ring A as distinct structural motifs. Their biological evaluation as inhibitors of human immunodeficiency virus type 1 replication revealed that two compounds from this series, 7 and 13, displayed strong inhibition of HIV-1 replication with IC50 values lower than 2 µM. Moreover, cellular mechanism experiments showed that the main target of these compounds in the HIV replication cycle is viral transcription. This study is the first report of withanolide-type steroids as HIV inhibitors and provides insight into their potential as candidates for further preclinical studies.
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Physalis/química , Replicação Viral/efeitos dos fármacos , Vitanolídeos/farmacologia , Linhagem Celular , El Salvador , HIV-1/fisiologia , Humanos , Estrutura Molecular , Componentes Aéreos da Planta/químicaRESUMO
As a part of our investigation into new anti-HIV agents, we report herein the isolation, structure elucidation, and biological activity of six new (1-6) and 20 known (7-26) pentacyclic lupane-type triterpenoids from the stem of Cassine xylocarpa and root bark of Maytenus cuzcoina. Their stereostructures were elucidated on the basis of spectroscopic and spectrometric methods, including 1D and 2D NMR techniques. To gain a more complete understanding of the structural requirements for anti-HIV activity, derivatives 27-48 were prepared by chemical modification of the main secondary metabolites. Sixteen compounds from this series displayed inhibitory effects of human immunodeficiency virus type 1 replication with IC50 values in the micromolar range, highlighting compounds 12, 38, and 42 (IC50 4.08, 4.18, and 1.70 µM, respectively) as the most promising anti-HIV agents.
Assuntos
Fármacos Anti-HIV/isolamento & purificação , Fármacos Anti-HIV/farmacologia , Celastraceae/química , Maytenus/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Fármacos Anti-HIV/química , Antineoplásicos Fitogênicos/química , HIV-1/efeitos dos fármacos , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Peru , Casca de Planta/química , Caules de Planta/química , Relação Estrutura-Atividade , Triterpenos/químicaRESUMO
Prevention methods to avoid transmission of pathogens, including HIV, are crucial in the control of infectious diseases, not only to block epidemic spread but to avoid long-term treatments leading to emergence of resistances and drug associated side effects. Together with vaccine development, the discovery of new virucidal agents represents a research priority in this setting. In the screening of new compounds with antiviral activity, three Guatemalan plant extracts from Justicia reptans, Neurolaena lobata and Pouteria viridis were evaluated with a classic antiviral assay and were found to inhibit HIV replication. This activity was corroborated by an original recombinant virus assay, leading us to perform a deeper study of the virucidal activity. Active fractions were non-toxic in vitro and also inhibited other enveloped viruses. Moreover, these fractions were able to inhibit the transfer of HIV from dendritic cells (DCs) to lymphocytes, that represents the main way of HIV spread in vivo.