RESUMEN
Four trimethylated acylphloroglucinols (5-8) have been isolated from maÌ nuka (Leptospermum scoparium) foliage. Apart from myrigalone A (8), which has previously been isolated from European bog myrtle (Myrica gale), these compounds have not been characterized before. The nortriketones are structurally similar to the bioactive tetramethylated ß-triketones from maÌ nuka, but have one less ring methyl group. Two oxidized trimethylated compounds, 9 and 10, were also isolated, but these are likely isolation artifacts. When evaluated for antibacterial activity against Gram-positive bacteria, myrigalone A (8) was slightly less potent (MIC 64 µg/mL) than the corresponding tetramethylated compound, grandiflorone (4) (MIC 16-32 µg/mL). Unlike their tetramethylated analogues, the nortriketones were inactive against the herbicide target enzyme p-hydroxyphenylpyruvate dioxygenase. The Raman spectra of leaf oil glands in different maÌ nuka varieties can be used to distinguish plants that contain nortriketones from those that accumulate triketones.
Asunto(s)
Antiinfecciosos/aislamiento & purificación , Leptospermum/química , Floroglucinol , 4-Hidroxifenilpiruvato Dioxigenasa/efectos de los fármacos , Antibacterianos , Antiinfecciosos/química , Antiinfecciosos/farmacología , Chalconas/química , Chalconas/aislamiento & purificación , Chalconas/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Enterococcus faecalis/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Bacterias Grampositivas , Herbicidas , Cetonas/análisis , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Nueva Zelanda , Resonancia Magnética Nuclear Biomolecular , Ácidos Fenilpirúvicos , Floroglucinol/análogos & derivados , Floroglucinol/química , Floroglucinol/aislamiento & purificación , Floroglucinol/farmacología , Hojas de la Planta/química , Vancomicina/farmacologíaRESUMEN
The molecular mechanism for 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) inhibition by nitisinone, a recently approved new drug for the treatment of hereditary tyrosinemia type I, has been satisfactorily explained by its action as an analogue to the substrate 4-hydroxyphenylpyruvate. In addition, a novel induced conformationally restricted 4-HPPD inhibitor, diketonitrile, which serves as a nonclassical bioisostere for rigid cyclic 1,3-diketone derivatives, has been introduced. Further application of the molecular mode of action of nitisinone in rational design of potential inhibitors for alpha-ketoglutarate-coupled dioxygenases is discussed.
Asunto(s)
4-Hidroxifenilpiruvato Dioxigenasa/efectos de los fármacos , Diseño de Fármacos , 4-Hidroxifenilpiruvato Dioxigenasa/antagonistas & inhibidores , 4-Hidroxifenilpiruvato Dioxigenasa/metabolismo , Ciclohexanonas/metabolismo , Ciclohexanonas/farmacología , Inhibidores Enzimáticos/metabolismo , Predicción , Isoxazoles/química , Isoxazoles/farmacología , Estructura Molecular , Nitrilos/metabolismo , Nitrobenzoatos/metabolismo , Nitrobenzoatos/farmacología , Oxigenasas/antagonistas & inhibidores , Oxigenasas/efectos de los fármacos , Oxigenasas/metabolismo , Sulfonas/metabolismo , Tirosinemias/tratamiento farmacológicoRESUMEN
The synthetic beta-triketones are a novel family of chemicals, developed as herbicides that have activity on grass and broadleaf weeds and are selective in corn. Toxicological evaluation of a number of these chemicals has established that they interfere with rat hepatic tyrosine catabolism in vivo by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD). This paper describes the kinetics of inhibition of rat hepatic HPPD in vitro by the representative beta-triketone 2-[2-nitro-4-(trifluoromethyl)benzoyl]-4,4,6,6- tetramethylcyclohexane-1,3,5-trione (1). A marked inhibition of rat hepatic HPPD was observed when 1 was incubated with the enzyme for 3 min at 37 degrees C prior to the initiation of the enzyme reaction by the addition of substrate. In this system, a concentration of 200 nM 1 resulted in a > 90% loss of HPPD activity, and an apparent IC50 was established at approximately 50 nM. The rate constant for the inactivation of HPPD by 1 was (1.5 +/- 0.2) x 10(-5) s-1 nM-1 as determined by progress curve data of oxygen consumed by HPPD with time. This inhibition is reversible in that the enzyme-inhibitor complex slowly dissociates, with approximately 5.5 +/- 0.6% of the enzyme activity being recovered by 6 h at 25 degrees C (t1/2, 25 degrees C, estimated at 101 +/- 14 h). In short, our studies establish 1 to be a tight-binding inhibitor of rat hepatic HPPD in vitro. This inhibition is characterized by the rapid inactivation of HPPD by the formation of an enzyme-inhibitor complex that dissociates extremely slowly with recovery of enzyme activity.