RESUMO
Porcine epidemic diarrhea virus (PEDV) has become increasingly problematic around the world, not only for its hazards to livestock but also due to the possibility that it is a zoonotic disease. Although vaccine therapy has made some progress toward PEDV control, additional effective therapeutic strategies against PEDV are needed, such as the development of chemotherapeutic agents. The aim of this work was to identify novel anti-PEDV agents by designing and synthesizing a series of phenanthridine derivatives. Among them, three compounds (compounds 1, 2, and 4) were identified as potent anti-PEDV agents exhibiting suppression of host cell heat shock cognate 70 (Hsc70) expression. Mechanism studies revealed that host Hsc70 is involved in the replication of PEDV, and its expression can be suppressed by destabilization of the mRNA, resulting in inhibition of PEDV replication. Activity against PEDV in vivo in PEDV-infected piglets suggested that phenanthridine derivatives are the first host-acting potential anti-PEDV agents.
Assuntos
Antivirais/farmacologia , Proteínas de Choque Térmico HSC70/metabolismo , Fenantridinas/farmacologia , Vírus da Diarreia Epidêmica Suína/efeitos dos fármacos , Animais , Antivirais/síntese química , Linhagem Celular , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/veterinária , Desenho de Fármacos , Estrutura Molecular , Fenantridinas/síntese química , SuínosRESUMO
Aphananoid A, a limonoid which features a rare C24 appendage and new 5/6/5 fused-ring framework, was obtained from Aphanamixis polystachya. The planar structure as well as the absolute configuration was identified based on extensive spectroscopic analysis and electronic circular dichroism calculations. The biogenetic pathway of aphananoid A was also speculated, which arises from the triterpene by the 3,4-seco-7,8-seco-6,8 cyclo-7,30-decarbon key pattern. In addition, bioassays indicated that aphananoid A inhibited NO production in the RAW264.7 cell line (46.80 ± 1.93%).
Assuntos
Limoninas , Meliaceae , Anti-Inflamatórios , Carbono , Limoninas/farmacologia , Estrutura Molecular , EsqueletoRESUMO
Phenanthridine derivativeHLY78 has previously been identified as the first Wnt/ß-catenin signalling pathway agonist that targets the DAX domain of axin. However, due to the relatively weak activation on the Wnt/ß-catenin signalling pathway, HLY78 is insufficient for further pharmacological study. Herein, the structural optimization of HLY78 and analyses of the structure-activity relationships (SARs) of HLY78-derived phenanthridine derivatives as agonists of the Wnt/ß-catenin signalling pathway are presented. In this work, 36 derivatives were designed and synthesized with some derivatives exhibiting stronger Wnt activity than the activity of HLY78. In particular, one of them, 8-((1,3-dimethy-pyrazol-5-yl)methoxy)-5-ethyl-4-methyl-5,6-dihydro-phenanthridin-9-ol, exhibited strong Wnt active activity and is 10 times more potent than HLY78. The following SAR analysis suggests that a pyrazole group, especially at the C-8 position, is important for Wnt activation; a methyl group at the C-4position seems to be more beneficial for Wnt activation than ethyl; and oxidation of the C-6 position reduces the Wnt activation.
Assuntos
Desenho de Fármacos , Fenantridinas/química , Proteínas Wnt/química , beta Catenina/química , Benzodioxóis/química , Sítios de Ligação , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Fenantridinas/metabolismo , Fenantridinas/farmacologia , Relação Estrutura-Atividade , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismoRESUMO
Lycorine is a benzylphenethylamine-type alkaloid member of the Amaryllidaceae family. A lycorine derivative, HLY78, was previously identified as a new Wnt/ß-catenin signaling pathway agonist that targets the DAX domain of axin. Herein, the structural optimization of HLY78 and analyses of the structure-activity relationships of lycorine-derived phenanthridine derivatives as agonists of the Wnt/ß-catenin signaling pathway are presented. This research suggests that triazole groups are important pharmacophores for Wnt activation; triazole groups at C-8 and C-9 of phenanthridine compounds markedly enhanced Wnt activation. A C-11-C-12 single bond is also important for Wnt activation. On the basis of these findings, two Wnt agonists were designed and synthesized. The results for these agonists indicated that the combination of a 4-ethyldihydrophenanthridine skeleton and a triazole substituent improves Wnt activation. These compounds may be useful in further pharmacological or biological studies.
Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Benzodioxóis/farmacologia , Fenantridinas/farmacologia , Triazóis/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Alcaloides de Amaryllidaceae/química , Benzodioxóis/química , Humanos , Estrutura Molecular , Fenantridinas/química , Fosforilação , Relação Estrutura-Atividade , Triazóis/química , Proteínas Wnt/metabolismo , beta Catenina/agonistasRESUMO
Introduction: Currently, the development of new antiviral drugs against COVID-19 remains of significant importance. In traditional Chinese medicine, the herb Euphorbia fischeriana Steud is often used for antiviral treatment, yet its therapeutic effect against the COVID-19 has been scarcely studied. Therefore, this study focuses on the roots of E. fischeriana Steud, exploring its chemical composition, antiviral activity against COVID-19, and the underlying basis of its antiviral activity. Methods: Isolation and purification of phytochemicals from E. fischeriana Steud. The elucidation of their configurations was achieved through a comprehensive suite of 1D and 2D NMR spectroscopic analyses as well as X-ray diffraction. Performed cytopathic effect assays of SARS-CoV-2 using Vero E6 cells. Used molecular docking to screen for small molecule ligands with binding to SARS-CoV-2 RdRp. Microscale thermophoresis (MST) was used to determine the dissociation constant Kd. Results: Ultimately, nine new ent-atisane-type diterpenoid compounds were isolated from E. fischeriana Steud, named Eupfisenoids A-I (compounds 1-9). The compound of 1 was established as a C-19-degraded ent-atisane-type diterpenoid. During the evaluation of these compounds for their antiviral activity against COVID-19, compound 1 exhibited significant antiviral activity. Furthermore, with the aid of computer virtual screening and microscale thermophoresis (MST) technology, it was found that this compound could directly bind to the RNA-dependent RNA polymerase (RdRp, NSP12) of the COVID-19, a key enzyme in virus replication. This suggests that the compound inhibits virus replication by targeting RdRp. Discussion: Through this research, not only has our understanding of the antiviral components and material basis of E. fischeriana Steud been enriched, but also the potential of atisane-type diterpenoid compounds as antiviral agents against COVID-19 has been discovered. The findings mentioned above will provide valuable insights for the development of drugs against COVID-19.
RESUMO
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented in human history. As a major structural protein, nucleocapsid protein (NPro) is critical to the replication of SARS-CoV-2. In this work, 17 NPro-targeting phenanthridine derivatives were rationally designed and synthesized, based on the crystal structure of NPro. Most of these compounds can interact with SARS-CoV-2 NPro tightly and inhibit the replication of SARS-CoV-2 in vitro. Compounds 12 and 16 exhibited the most potent anti-viral activities with 50% effective concentration values of 3.69 and 2.18 µM, respectively. Furthermore, site-directed mutagenesis of NPro and Surface Plasmon Resonance (SPR) assays revealed that 12 and 16 target N-terminal domain (NTD) of NPro by binding to Tyr109. This work found two potent anti-SARS-CoV-2 bioactive compounds and also indicated that SARS-CoV-2 NPro-NTD can be a target for new anti-virus agents.
Assuntos
Antivirais/química , Proteínas do Nucleocapsídeo de Coronavírus/antagonistas & inibidores , Fenantridinas/química , SARS-CoV-2/metabolismo , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , Sítios de Ligação , COVID-19/virologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Desenho de Fármacos , Humanos , Cinética , Simulação de Acoplamento Molecular , Fenantridinas/metabolismo , Fenantridinas/farmacologia , Fenantridinas/uso terapêutico , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Células Vero , Tratamento Farmacológico da COVID-19RESUMO
Two new sesquiterpenoids were isolated from Stellera chamaejasme L., known as the traditional Chinese herb 'Rui Xiang Lang Du'. The compounds were elucidated as stelleraguaianone B (1) and C (2) by comprehensive spectroscopic analysis, including 1D and 2D NMR as well as HRESIMS, and by comparing their NMR data with known compounds. In addition, the structure of 1 was further confirmed by single-crystal X-ray diffraction analysis. Both the compounds were evaluated for their cytotoxicity on common tumour cell lines in vitro, which revealed that compound 1 exhibits cytotoxic activity on A549 cells, while 2 has no activity.