RESUMEN
BACKGROUND AND PURPOSE: Pharmacological strategies aimed to facilitate neuronal renewal in the adult brain, by promoting endogenous neurogenesis, constitute promising therapeutic options for pathological or traumatic brain lesions. We have previously shown that non-tumour-promoting PKC-activating compounds (12-deoxyphorbols) promote adult neural progenitor cell (NPC) proliferation in vitro and in vivo, enhancing the endogenous neurogenic response of the brain to a traumatic injury. Here, we show for the first time that a diterpene with a lathyrane skeleton can also activate PKC and promote NPC proliferation. EXPERIMENTAL APPROACH: We isolated four lathyranes from the latex of Euphorbia plants and tested their effect on postnatal NPC proliferation, using neurosphere cultures. The bioactive lathyrane ELAC (3,12-di-O-acetyl-8-O-tigloilingol) was also injected into the ventricles of adult mice to analyse its effect on adult NPC proliferation in vivo. KEY RESULTS: The lathyrane ELAC activated PKC and significantly increased postnatal NPC proliferation in vitro, particularly in synergy with FGF2. In addition ELAC stimulated proliferation of NPC, specifically affecting undifferentiated transit amplifying cells. The proliferative effect of ELAC was reversed by either the classical/novel PKC inhibitor Gö6850 or the classical PKC inhibitor Gö6976, suggesting that NPC proliferation is promoted in response to activation of classical PKCs, particularly PKCß. ELAC slightly increased the proportion of NPC expressing Sox2. The effects of ELAC disappeared upon acetylation of its C7-hydroxyl group. CONCLUSIONS AND IMPLICATIONS: We propose lathyranes like ELAC as new drug candidates to modulate adult neurogenesis through PKC activation. Functional and structural comparisons between ELAC and phorboids are included.
Asunto(s)
Diterpenos/farmacología , Células-Madre Neurales/efectos de los fármacos , Proteína Quinasa C beta/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Diterpenos/química , Diterpenos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Ratones , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Three new, highly functionalized ingol diterpenes, ingol 7,8,12-triacetate 3-phenylacetate (1), ingol 7,8,12-triacetate 3-(4-methoxyphenyl)acetate (2) and 8-methoxyingol 7,12-diacetate 3-phenylacetate (3), together with the novel spirotriterpene, 3S,4S,5R,7S,9R,14R-3,7-dihydroxy-4,14-dimethyl-7[8-->9]-Abeo-cholestan-8-one (4), have been isolated from Euphorbia officinarum latex. Structures were established on the basis of their spectroscopic data, including two-dimensional NMR analysis and NOE experiments. The biological effects of 1-3 on cell cycle and HIV-1 gene transcription were analysed in the Jurkat T cell line. Compound 3 induced cell-cycle arrest and HIV-1-LTR promoter activation and could represent a novel lead compound for the development of therapies against HIV-1 latency.
Asunto(s)
Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Euphorbia/química , VIH-1/efectos de los fármacos , Fenilacetatos/aislamiento & purificación , Fenilacetatos/farmacología , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/farmacología , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Latencia del Virus/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Cristalografía por Rayos X , Citometría de Flujo , Regulación Viral de la Expresión Génica/efectos de los fármacos , VIH-1/genética , Humanos , Indicadores y Reactivos , Células Jurkat , Látex/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
[reaction: see text] The biosynthetic origin of the botcinolide skeleton was investigated by means of feeding 13C- and 2H-labeled precursors to Botrytis cinerea. Three new compounds, two homobotcinolide derivatives, 3-O-acetylhomobotcinolide (5) and 8-methylhomobotcinolide (6), and a new 11-membered lactone (7), were isolated. Their structures were elucidated on the basis of spectroscopic data, including one-bond and long-range 1H-13C correlations. The relative stereochemistries were determined by combined analyses of NOE data and 1H-1H coupling constants. According to the results of feeding experiments with 13C- and 2H-labeled acetate and l-S-methylmethionine, 5 is an acetate-derived polyketide whose methyl groups originate from l-S-methylmethionine. This is a rare example of the incorporation of a methyl from methionine into a supposed C3 starter unit of the polyketide synthesis.
Asunto(s)
Botrytis/química , Lactonas/química , Acetatos , Botrytis/crecimiento & desarrollo , Hidroxilación , Lactonas/aislamiento & purificación , Metionina , Modelos Moleculares , Conformación MolecularRESUMEN
Eleven beta-himachalene derivatives were tested, using the poisoning food technique, for their potential antifungal activity against the phytopathogen Botrytis cinerea. Compounds 1-11 displayed moderate activity, whereas the 6,7-diol derivative (12) produced an inhibition of 91% after 6 days. The microbial transformation of 12 was investigated and yielded four new compounds hydroxylated at positions C-5 (13), C-2 (14), C-4 (15), and C-12 (16). The structures were established on the basis of their spectroscopic data including two-dimensional NMR analysis (HMQC, HMBC, nOesy) and nOes. The results obtained from biotransformation experiments shed further light on the detoxification mechanism of the phytopathogenic fungus against this compound and give an indication of the structural modifications that may be necessary if substrates of this type are to be further developed as selective fungal control agents for B. cinerea.
Asunto(s)
Benzoatos/metabolismo , Botrytis/efectos de los fármacos , Botrytis/metabolismo , Compuestos Epoxi/metabolismo , Fungicidas Industriales/farmacología , Benzoatos/química , Benzoatos/farmacología , Compuestos Epoxi/química , Compuestos Epoxi/farmacología , Fungicidas Industriales/metabolismo , Espectroscopía de Resonancia Magnética , Estructura Molecular , SesquiterpenosRESUMEN
Diisophorone (1) was tested against two strains of the necrotrophic plant pathogen Botrytis cinerea. Fungal sensitivity varied according to the strain. B. cinera 2100 was more sensitive than B. cinereaUCA992: its mycelial growth was significantly inhibited at concentrations of 50 ppm and above. Although diisophorone (1) showed an effective control of B. cinerea, a detoxification mechanism was present. The detoxification of racemic diisophorone (1) by B. cinerea was investigated. Incubation with two strains of B. cinerea gave one and four biotransformation products (2-5), respectively. Their structures were established as the known 8beta-hydroxydiisophorone (2), 6alpha-hydroxydiisophorone (3), 6beta-hydroxydiisophorone (4) and 8beta,14beta-dihydroxydiisophorone (5) on the basis of their spectroscopic data, including two-dimensional NMR analysis [heteronuclear multiple quantum coherence (HMQC), heteronuclear multiple bond correlation (HMBC), and nuclear Overhauser enhancement spectroscopy (NOESY)] and an X-ray crystallographic study.
Asunto(s)
Botrytis/efectos de los fármacos , Botrytis/metabolismo , Ciclohexanonas/metabolismo , Ciclohexanonas/farmacología , Fungicidas Industriales/metabolismo , Fungicidas Industriales/farmacología , Biotransformación , Botrytis/crecimiento & desarrollo , Ciclohexanonas/química , Hidroxilación , Espectroscopía de Resonancia Magnética , Estructura Molecular , Micelio/crecimiento & desarrollo , Plantas/microbiologíaRESUMEN
An efficient, one-pot synthesis of angular and linear dihydropyranocoumarins, along with C-6 and C-8 prenylated coumarins is reported. These compounds, together with single- and furanocoumarins, were tested for their potential antifungal activity against the phytopathogen Botrytis cinerea Pers ex Fr. The results show that furanocoumarins may be able to control the fungus B cinerea.
Asunto(s)
Factores Biológicos/toxicidad , Botrytis/efectos de los fármacos , Cumarinas/toxicidad , Fungicidas Industriales/toxicidad , Control Biológico de Vectores/métodos , Factores Biológicos/síntesis química , Cumarinas/síntesis química , Técnicas de Cultivo , Fungicidas Industriales/síntesis química , Furocumarinas/síntesis química , Furocumarinas/toxicidad , Prenilación de ProteínaRESUMEN
Two novel steroids, 3beta,7alpha-dihydroxy-4alpha,14alpha-dimethyl-5alpha-cholest-8-en-11-one (2) and 3beta,7beta-dihydroxy-4alpha,14alpha-dimethyl-5alpha-cholest-8-en-11-one (3) were isolated from the latex of Euphorbia officinarum. Their structures were established on the basis of NMR and MS studies.