RESUMEN
Two dimeric sesquiterpenes were separated from Chloranthus japonicus Sieb. and identified as shizukaols C and F. They exhibited potent antifungal activities (MICs = 4-16 µg/ml) in vitro against various plant pathogenic fungi (Pythium ultimum, Phytophthora infestans, Botrytis cinerea, Colletotrichum lagenarium, Alternaria kikuchiana, and Magnaporthe grisea). Shizukaol C showed 88% and 91% protective activities in the greenhouse against Puccinia recondita (wheat leaf rust) and Phytophthora infestans (tomato late blight), respectively, at 100 µg/ml; shizukaol F exhibited 93% antifungal activity against Puccinia recondita at the same concentration. Therefore, these compounds might serve as interesting candidates for effective antifungal agents.
Asunto(s)
Antifúngicos/farmacología , Hongos/efectos de los fármacos , Magnoliopsida/química , Sesquiterpenos/farmacología , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Fungicidas Industriales/aislamiento & purificación , Fungicidas Industriales/farmacología , Medicina Tradicional China , Pruebas de Sensibilidad Microbiana , Phytophthora infestans/efectos de los fármacos , Enfermedades de las Plantas/prevención & control , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificaciónRESUMEN
In the course of search for potent chitin synthase inhibitors from plant extracts, the chitin synthase 2 inhibitors, O-methyl pisiferic acid and 8,20-dihydroxy-9(11),13-abietadien-12-one which have diterpene skeleton, were isolated from the leaves of Chamaecyparis pisifera. These compounds inhibited chitin synthase 2 of Saccharomyces cerevisiae with the IC50 values of 5.8 and 226.4 microM, respectively. Especially, O-methyl pisiferic acid showed 15.3-fold stronger inhibitory activity than polyoxin D (IC50=88.6 microM), a well-known chitin synthase inhibitor. These compounds exhibited weaker inhibitory activities against chitin synthase 1 than chitin synthase 2, whereas it showed no inhibitory activity for chitin synthase 3. The compound exhibited mixed competitive inhibition with respect to UDP-N-acetyl-D-glucosamine as substrate (Ki=5 microM). These results indicated that O-methyl pisiferic acid is a specific inhibitor of chitin synthase 2. The compound also inhibited chitin synthase 1 of Candida albicans, which represents analogues to chitin synthase 2 of S. cerevisiae, with an IC50 of 75.6 microM, which represents 1.8-fold weaker activity than that of polyoxin D. Although O-methyl pisiferic acid has been reported for antibacterial and insecticidal activities, the present study is the first report on its inhibitory activity against chitin synthase 2.
Asunto(s)
Abietanos/farmacología , Antifúngicos/farmacología , Chamaecyparis/química , Quitina Sintasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Abietanos/aislamiento & purificación , Antifúngicos/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/aislamiento & purificación , Hongos/efectos de los fármacos , Cinética , Espectroscopía de Resonancia Magnética , Membranas/efectos de los fármacos , Membranas/enzimología , Pruebas de Sensibilidad Microbiana , Hojas de la Planta/química , Saccharomyces cerevisiae/enzimología , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Potent chitin synthase 2 inhibitors, methyllinderone (1), linderone (2) and kanakugiol (3) were isolated from the stem bark of L. erythrocarpa Makino (Lauraceae). These compounds inhibited chitin synthase 2 with IC(50) values of 23.3, 21.4 and 23.8 microg/mL, respectively. Methyllinderone (1) and linderone (2) exhibited no inhibitory activities for chitin synthases 1 and 3 from S. cerevisiae, and chitin synthase 1 from Candida albicans up to the concentration of 280 microg/mL, while kanakugiol (3) exhibited very weak activity against chitin synthase 1 of C. albicans with an IC(50) of 160 microg/mL. All of the compounds showed moderate to weak antifungal activities against various pathogenic fungi (MIC: 8 - >128 microg/mL) including Cryptococcus neoformans, Aspergillus fumigatus, and Colletotrichum lagenarium. The results indicate that these compounds are specific inhibitors of chitin synthase 2 and can potentially serve as antifungal agents.
Asunto(s)
Antifúngicos/farmacología , Quitina Sintasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Lindera , Fitoterapia , Extractos Vegetales/farmacología , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Candida albicans/efectos de los fármacos , Candida albicans/enzimología , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Humanos , Concentración 50 Inhibidora , Lignanos/administración & dosificación , Lignanos/farmacología , Lignanos/uso terapéutico , Pruebas de Sensibilidad Microbiana , Hongos Mitospóricos/efectos de los fármacos , Corteza de la Planta , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéuticoRESUMEN
In the course of search for potent chitin synthase inhibitors from natural resources, a novel chitin synthases inhibitor, 2'-benzoyloxycinnamaldehyde (2'-BCA) (I), was isolated from the aerial parts of Pleuropterus ciliinervis NAKAI. 2'-BCA inhibited chitin synthase 1 and 2 of Saccharomyces cerevisiae with the IC50s of 54.9 and 70.8 microg/ml, respectively, whereas it exhibited no inhibitory activity for chitin synthase 3 up to 280 microg/ml. Its derivatives, 2'-chloro- (V) and 2(-bromo-cinnamaldehyde (VI), each showed 1.9 and 2.7-fold stronger inhibitory activities than 2'-BCA, with the IC50s of 37.2 and 26.6 microg/ml, respectively. Especially, the IC50 of compound VI against chitin synthase 2 represented 1.7-fold more potent inhibitory activity than polyoxin D, a well-known chitin synthase inhibitor. Furthermore, compounds V and VI showed potent antifungal activities against various fungi including human pathogenic fungi, with a particularly strong inhibitory activity against Cryptococcus neoformans (MIC = 16 microg/ml). Although the chemical synthesis of this compound has been reported, the present study is the first report to describe the isolation of 2'-BCA from natural resources and chitin synthases inhibitory activities of its derivatives. These results suggested that 2'-BCA and its derivatives can potentially serve as useful lead compounds for development of antifungal agents.
Asunto(s)
Acroleína/análogos & derivados , Antifúngicos/farmacología , Benzoatos/farmacología , Quitina Sintasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Polygonaceae/química , Acroleína/química , Acroleína/aislamiento & purificación , Acroleína/farmacología , Aminoglicósidos/farmacología , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Benzoatos/química , Benzoatos/aislamiento & purificación , Candida/efectos de los fármacos , Candida/crecimiento & desarrollo , Quitina Sintasa/metabolismo , Cryptococcus neoformans/efectos de los fármacos , Cryptococcus neoformans/crecimiento & desarrollo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Estructura Molecular , Componentes Aéreos de las Plantas/química , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Nucleósidos de Pirimidina/farmacologíaRESUMEN
Phellinsin A, which was isolated from the culture broth of Phellinus sp. PL3, exhibited significant low-density lipoproteins (LDL)-antioxidant activity. It inhibited the Cu2+-mediated oxidation of LDL (IC50: 5.3 microM) and 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH)-mediated oxidation of LDL (IC50: 2.8 microM) in the thiobarbituric acid-reactive substances (TBARS) assay as well as the macrophage-mediated LDL oxidation (73% inhibition at 5 microM). In addition, it delayed LDL oxidation with a prolonged lag time (192 min at 2 microM, control: 44 min). This compound also showed a 10-fold more potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity (IC50: 1.7 microM) than trolox (IC50: 18.6 microM), a known DPPH inhibitor. In addition, phellinsin A inhibited xanthine oxidase activity with an IC50 value of 31.0 microM, whereas allopurinol, a xanthine oxidase inhibitor, showed an IC50 value of 40.7 microM.
Asunto(s)
Agaricales , Anticolesterolemiantes/farmacología , Antioxidantes/farmacología , LDL-Colesterol/efectos de los fármacos , Lactonas/farmacología , Fenoles/farmacología , Fitoterapia , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/uso terapéutico , Antioxidantes/administración & dosificación , Antioxidantes/uso terapéutico , Compuestos de Bifenilo , Humanos , Concentración 50 Inhibidora , Lactonas/administración & dosificación , Lactonas/uso terapéutico , Fenoles/administración & dosificación , Fenoles/uso terapéutico , Picratos/química , Sustancias Reactivas al Ácido Tiobarbitúrico/químicaRESUMEN
In the course of the search for inhibitors of ScCHS2 from natural sources, we have isolated a new type of chitin synthase 2 inhibitor, obovatol, which has a biphenol skeleton, from Magnolia obovata. Obovatol inhibited chitin synthase 2 activity of Saccharomyces cerevisiae with an IC(50) of 38 microM. Its derivative, tetrahydroobovatol, inhibited chitin synthase 2 activity under the same conditions with an IC(50) of 59 microM. These compounds exhibited no inhibitory activity for ScCHS3, and showed less inhibitory activity for chitin synthase 1 than for chitin synthase 2 (IC(50) > 1 mM). These results indicated that obovatol and tetrahydroobovatol are specific inhibitors of ScCHS2. They also inhibited CaCHS1, which is structurally and functionally analogous to ScCHS2, with similar IC(50)s to ScCHS2 (IC(50) 28 and 51 microM, respectively). The compounds exhibited mixed competitive inhibition with respect to UDP-N-acetyl-D-glucosamine as substrate [inhibition constant (K(i)) 21.8 microM for obovatol and 23.1 microM for tetrahydroobovatol]. Furthermore, they showed antifungal activities against various pathogenic fungi, with a particularly strong inhibitory activity against Cryptococcus neoformans (MIC 7.8 mg/L). The results indicate that obovatol and tetrahydroobovatol can potentially serve as antifungal agents.