RESUMEN
The 70 % EtOH extract of Polygonum cuspidatum showed inhibitory action against HIV-1-induced syncytium formation at non-cytotoxic concentrations in vitro with a 50 % effective concentration (EC(50)) of 13.94 +/- 3.41 microg/mL. Through bioactivity-guided fractionation, 20 phenolic compounds, including eight stilbenoids, were isolated from the roots of Polygonum cuspidatum, and their anti-HIV-1 activities were evaluated. Results showed that compounds 1, 13, 14, and 16 demonstrated fairly strong antiviral activity against HIV-1-induced cytopathic effects in C8166 lymphocytes at non-cytotoxic concentrations, with EC (50) values of 4.37 +/- 1.96 microg/mL, 19.97 +/- 5.09, 14.4 +/- 1.34 microg/mL, and 11.29 +/- 6.26 microg/mL and therapeutic index (TI) values of 8.12, > 10.02, > 13.89, and > 17.71, respectively. Other compounds showed either weak or no effects. Compound 6 also showed weak inhibition (153.42 +/- 19.25 microg/mL); however, it possesses very good water solubility and showed almost no cytotoxicity (> 2000 microg/mL), therefore achieving a fairly good TI (13.04). The activities of the two compounds (3 and 18) from Polygonum multiflorum were also assayed. The relationship between molecular structures and their bioactivities was also discussed.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Fallopia japonica/química , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Fenoles/uso terapéutico , Extractos Vegetales/uso terapéutico , Polygonum/química , Fármacos Anti-VIH/aislamiento & purificación , Fármacos Anti-VIH/farmacología , Infecciones por VIH/virología , Humanos , Fenoles/aislamiento & purificación , Fenoles/farmacología , Fitoterapia , Extractos Vegetales/química , Extractos Vegetales/farmacología , Raíces de Plantas , Estilbenos/aislamiento & purificación , Estilbenos/farmacología , Estilbenos/uso terapéuticoRESUMEN
Natural (-)-huperzine B (HupB), isolated from Chinese medicinal herb, displayed moderate inhibitory activity of acetylcholinesterase (AChE). Based on the active dual-site of AChE, a series of novel derivatives of bis- and bifunctional HupB were designed and synthesized. The AChE inhibition potency of most derivatives of HupB was enhanced about 2-3 orders of magnitude as compared with the parental HupB. Among bis-HupB derivatives, 12h exhibited the most potent in the AChE inhibition and has been evaluated for its pharmacological actions in vivo on ChE inhibition, cognitive enhancement, and neuroprotection. The docking study on the bis-HupB derivatives 12 series with TcAChE has demonstrated that the ligands bound to the dual-site of the enzyme in different level.
Asunto(s)
Acetilcolinesterasa/química , Alcaloides/farmacología , Butirilcolinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Alcaloides/síntesis química , Alcaloides/química , Animales , Sitios de Unión , Butirilcolinesterasa/sangre , Corteza Cerebral/enzimología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Ratas , Relación Estructura-ActividadRESUMEN
The 3C-like proteinase (3CLpro) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for anti-SARS-CoV drugs due to its crucial role in the viral life cycle. In this study, a database containing structural information of more than 8,000 existing drugs was virtually screened by a docking approach to identify potential binding molecules of SARS-CoV 3CLpro. As a target for screening, both a homology model and the crystallographic structure of the binding pocket of the enzyme were used. Cinanserin (SQ 10,643), a well-characterized serotonin antagonist that has undergone preliminary clinical testing in humans in the 1960s, showed a high score in the screening and was chosen for further experimental evaluation. Binding of both cinanserin and its hydrochloride to bacterially expressed 3CLpro of SARS-CoV and the related human coronavirus 229E (HCoV-229E) was demonstrated by surface plasmon resonance technology. The catalytic activity of both enzymes was inhibited with 50% inhibitory concentration (IC50) values of 5 microM, as tested with a fluorogenic substrate. The antiviral activity of cinanserin was further evaluated in tissue culture assays, namely, a replicon system based on HCoV-229E and quantitative test assays with infectious SARS-CoV and HCoV-229E. All assays revealed a strong inhibition of coronavirus replication at nontoxic drug concentrations. The level of virus RNA and infectious particles was reduced by up to 4 log units, with IC50 values ranging from 19 to 34 microM. These findings demonstrate that the old drug cinanserin is an inhibitor of SARS-CoV replication, acting most likely via inhibition of the 3CL proteinase.
Asunto(s)
Antivirales/farmacología , Cinanserina/farmacología , Inhibidores de Proteasas/farmacología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/enzimología , Proteínas Virales/antagonistas & inhibidores , Animales , Antivirales/química , Secuencia de Bases , Línea Celular , Chlorocebus aethiops , Cinanserina/química , Proteasas 3C de Coronavirus , Cricetinae , Cisteína Endopeptidasas , ADN Viral/genética , Evaluación Preclínica de Medicamentos/métodos , Endopeptidasas/química , Endopeptidasas/genética , Humanos , Técnicas In Vitro , Modelos Moleculares , Inhibidores de Proteasas/química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , Interfaz Usuario-Computador , Células Vero , Proteínas Virales/química , Proteínas Virales/genética , Replicación Viral/efectos de los fármacosRESUMEN
By targeting dual active sites of AChE, a number of new derivatives of HupB have been synthesized and tested as acetylcholinesterase inhibitors. The most potent compound, bis-HupB 5b is 72-fold more potent in AChE inhibition and 79-fold more selective for AChE versus BChE than HupB.
Asunto(s)
Alcaloides/síntesis química , Inhibidores de la Colinesterasa/síntesis química , Alcaloides/farmacología , Animales , Sitios de Unión , Corteza Cerebral , Inhibidores de la Colinesterasa/farmacología , Medicamentos Herbarios Chinos/síntesis química , Medicamentos Herbarios Chinos/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
HupA is a potent, reversible AChEI, which crosses the blood-brain barrier smoothly, and shows high specificity for AChE with a prolonged biological half-life. It has been approved as the drug for the treatment of AD in China, and marketed in USA as a dietary supplement. HupA has been the subject of investigations by an ever-increasing number of researchers since 1980's. In the last four years, HupA has been further studied in many aspects such as the chemical synthesis, structural modification, structure-activity relationship, various biological effects, and mechanisms of action. A number of papers dealing with the computational modeling and X-ray crystallographic studies of HupA-AChE complex have also been published. This review represents a comprehensive documentation of the progress in the studies on HupA during the period of 1999-2002.
Asunto(s)
Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Sesquiterpenos/química , Sesquiterpenos/farmacología , Alcaloides , Animales , Ensayos Clínicos como Asunto , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Fármacos Neuroprotectores/uso terapéutico , Sesquiterpenos/uso terapéutico , Relación Estructura-ActividadRESUMEN
AIM: To study asymmetric total synthesis of 14-nor-huperzine A 2 and its inhibitory activity on acetylcholinesterase. METHODS: Highly enantioselective synthesis of compound 5 from beta-keto-ester 3 and 2-methylene-1,3-propanediol diacetate 4 by palladium-catalyzed bicycloannulation was carried out using new chiral ferrocenylphosphine ligands, such as 10, 11, followed by regioselective double-bond migration to produce compound 6. Optically pure 6 was obtained after enantio-enrichment recrystallization. Then, according to similar procedures of huperzine A synthesis, the target compound 14-nor-huperzine A 2 was prepared. The inhibitory activity was tested with rat erythrocyte membrame acetylcholinesterase. RESULTS: The inhibitory activity of synthetic (-)-14-nor-huperzine A was 8 fold less potent than that of (-)-huperzine A. CONCLUSION: A hydrogen-bond between 14-methyl group of (-) huperzine A and the main-chain oxygen of His 440 is necessary for the highly acetylcholinesterase inhibitory activity of huperzine A.
Asunto(s)
Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Sesquiterpenos/síntesis química , Alcaloides , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Membrana Eritrocítica/efectos de los fármacos , Membrana Eritrocítica/enzimología , Conformación Molecular , Estructura Molecular , Ratas , Sesquiterpenos/química , Sesquiterpenos/farmacología , Sesquiterpenos/uso terapéuticoRESUMEN
A number of aglycon analogues of sarmentosin were prepared and their bioactivities on the proliferation of T-lymphocytes and B-lymphocytes were assayed.
Asunto(s)
Glucosa/análogos & derivados , Glucosa/síntesis química , Activación de Linfocitos/efectos de los fármacos , Nitrilos/síntesis química , Animales , Linfocitos B/efectos de los fármacos , División Celular/efectos de los fármacos , Glucosa/farmacología , Humanos , Hidrocarburos Aromáticos , Ratones , Ratones Endogámicos ICR , Nitrilos/farmacología , Extractos Vegetales/síntesis química , Extractos Vegetales/farmacología , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacosRESUMEN
Two lignan sulfates, a stilbene derivative and a phenol sulfate, together with 10 known compounds, were isolated from an aqueous extract of the root of Polygonum cuspidatum. The new compounds were elucidated based on chemical evidence and spectroscopic techniques including two-dimensional NMR methods. They exhibited no inhibition of lipid peroxidation and no cytotoxic and DNA cleavage activities.