RESUMEN
The human phosphatidylinositol 4-phosphate 5-kinase type I α (hPIP5K1α) plays a key role in the development of prostate cancer. In this work, seventeen derivatives of the natural diterpene totarol were prepared by copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of the correspondingO-propargylated totarol with aryl or alkyl azides and screened for their inhibitory activities toward hPIP5K1α. Five compounds, 3a, 3e, 3f, 3i, and 3r, strongly inhibited the enzyme activity with IC50 values of 1.44, 0.46, 1.02, 0.79, and 3.65 µM, respectively, with the most potent inhibitor 3e 13-[(1-(3-nitrophenyl)triazol-4yl)methoxy]-totara-8,11,13-triene). These compounds were evaluated on their antiproliferative effects in a panel of prostate cancer cell lines. Compound 3r inhibited the proliferation of LNCaP, PC3 and DU145 cells at 20 µM, strongly, but also has strong cytotoxic effects on all tested cells.
Asunto(s)
Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Fosfotransferasas (Aceptor de Grupo Alcohol) , Triazoles , Humanos , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Estructura Molecular , Diterpenos/farmacología , Diterpenos/química , Diterpenos/síntesis química , Relación Dosis-Respuesta a Droga , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Simulación del Acoplamiento MolecularRESUMEN
From aerial parts of Austroeupatorium inulifolium was isolated the ent-nor-furano triol labdane austroeupatol 1. The compound 1 was treated with IBX showing an unexpected selectivity at the potentially oxidizable sites of the substrate yielding the 2-oxoaustroeupatol (2) and 2,19-dioxoaustroeupatol (3). The treatment of 2 with sodium periodate yields a heterocyclic derivative (ε-caprolactone derivate 4) formed by oxidative cleavage and unexpected intramolecular attack of the hydroxymethylene (C-19) oxygen to the ketonic carbon (C-2). A plausible mechanistic pathway for the obtention of compound 4 is proposed.
RESUMEN
From aerial parts of Stevia lucida Lagasca was isolated the natural mixture of isomeric eudesmanolides helenin. The identification and quantification of the constituents of helenin (alantolactone 1 and isoalantolactone 2, ratio 3:7) was performed through the quantitative analysis of its 1D and 2D NMR spectra.
Asunto(s)
Sesquiterpenos de Eudesmano , Stevia , Lactonas , SesquiterpenosRESUMEN
Basic hydrolysis of a dichloromethane extract of Stevia lucida yielded (4R,5S,7R,9R,10R,11R)-7,9-dihydroxylongipin-2-en-1-one (1), which was oxidized and subjected to acidic conditions to generate the new seco-moreliane derivative 3. The structure of 3 was established based on NMR data interpretation and confirmed computationally. A plausible mechanism for the carbocationic rearrangement of the trione 2 to the seco-moreliane 3 was supported by DFT computations.
Asunto(s)
Sesquiterpenos/aislamiento & purificación , Stevia/química , Hidrólisis , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Oxidación-Reducción , Sesquiterpenos/química , Estereoisomerismo , VenezuelaRESUMEN
The incubation of 15α-hydroxy-ent-kaur-9(11),16-dien-19-oic acid (15α-hydroxy-grandiflorenic acid) with the fungus Fusarium fujikuroi gave as main metabolite its 3ß,6ß-dihydroxy derivative, which by an oxidative decarboxylation afforded a 19-nor compound with a 4,18-double bond. Other substances obtained were a 3α-hydroxy-19,6α-lactone, 3ß-hydroxy-6ß,7ß-epoxy-ent-kaur-9(11),16-dien-19-oic acid and 3ß-hydroxy-6-oxo-ent-kaur-9(11),16-dien-19-oic acid. Moreover, the biotransformation of 15α,18-dihydroxy-ent-kaur-9(11),16-diene led to the isolation of the corresponding 3ß-, 6ß-, 7α- and 12ß-hydroxy derivatives. Two metabolites formed by 16ß,17-epoxidation of the last compound and of the substrate were also obtained. These results indicated that the presence of the 9,11-double bond in the substrate impedes its 7ß-hydroxylation, which is necessary for the formation of gibberellins and seco-ring B ent-kaurenoids. However, this 9,11-unsaturation does not hinder a 6,7-dehydrogenation and further 6ß,7ß-epoxidation, characteristic steps of the kaurenolide biosynthetic pathway.
Asunto(s)
Diterpenos/química , Diterpenos/metabolismo , Fusarium/metabolismo , BiotransformaciónRESUMEN
A series of kaurene derivatives (1-63) were prepared and evaluated for anti-inflammatory activity. Thirteen of the tested compounds were able to inhibit NO production with an IC(50) between 2 and 10 µM. Compounds 11, 12, 14 and 23 showed low percentage of cell viability, whereas compounds 9, 10, 17, 28, 37, 48, 55, 61 and 62 were non-cytotoxic at the concentration up to 25 µM. Some structure-activity relationships were outlined. Compounds 28, 55 and 62, were selected as representative compounds and they potently inhibited the protein expression of NOS-2. We also determined that inhibition of NF-κB activation might be the mechanism involved in anti-inflammatory effects of these kaurene derivatives. As expected, cytokines IL-6, IL-1α, TNF-α and IFN-γ were downregulated in the presence of compound 28, 55 and 62 after stimulation with LPS. These results indicate that kaurene derivatives might be used for the design of new anti-inflammatory agents.
Asunto(s)
Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/farmacología , Animales , Antiinflamatorios/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Diterpenos de Tipo Kaurano/química , Regulación de la Expresión Génica/efectos de los fármacos , Lipopolisacáridos/farmacología , Ratones , FN-kappa B/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismoRESUMEN
In the present study, a series of labdane derivatives (2-9) were prepared from labdanediol (1) and their potential as anti-inflammatory agents were evaluated on lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. All compounds were able to inhibit LPS-induced nitric oxide (NO), although compounds 1, 2, 5, 8 and 9 exhibited the most potent effects with a range of IC(50) values of 5-15 microM. Similarly to the inhibitory effects on NO release, these labdane derivatives also inhibited prostaglandin E(2) (PGE(2)) production. However, analysis of cell viability demonstrated that effects on NO release and (PGE(2)) production of compounds 1, 8 and 9 were due to citotoxicity, whereas compound 2 and 5 did not show any effect in the survival of RAW 264.7 macrophages. In addition to these in vitro data, compound 5 also showed anti-inflammatory activity in vivo, when tested in mice. They prevented the extent of swelling in the TPA-induced ear edema model and inhibited MPO activity, showing similar potency to that of the widely used anti-inflammatory drug indomethacin. These results indicate that compound 2 and in particular compound 5 might be used for the design of new anti-inflammatory agents.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Diterpenos/química , Diterpenos/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/uso terapéutico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Dinoprostona/biosíntesis , Diterpenos/síntesis química , Diterpenos/uso terapéutico , Edema/tratamiento farmacológico , Concentración 50 Inhibidora , Masculino , Ratones , Óxido Nítrico/biosíntesisRESUMEN
Thirty one ent-kaurane derivatives were prepared from kaurenoic acid (1), grandiflorenic acid (16), 15alpha-acetoxy-kaurenoic acid (26) and 16alpha-hydroxy-kaurenoic acid (31). They were tested for their ability to inhibit cell viability in the mouse leukemic macrophagic RAW 264.7 cell line. The most effective compounds were 12, 20, 21, and 23. These were selected for further evaluation in other human cancer cell lines such as Hela, HepG2, and HT-29. Similar effects were obtained although RAW 264.7 cells were more sensitive. In addition, these compounds were significantly less cytotoxic in non-transformed cells. The apoptotic potential of the most active compounds was investigated and they were able to induce apoptosis with compound 12 being the best inducer. The caspase-3, -8 and -9 activities were measured. The results obtained showed that compounds 12, 21, and 23 induce apoptosis via the activation of caspase-8, whereas compound 20 induces apoptosis via caspase-9. Immunoblot analysis of the expression of p53, Bax, Bcl-2, Bcl-xl, and IAPs in RAW 264.7 cells was also carried out. When cells were exposed to 5 microM of the different compounds, expression levels of p53 and Bax increased whereas levels of antiapoptotic proteins such as Bc1-2, Bc1-x1, and IAPs decreased. In conclusion, kaurane derivatives (12, 20, 21, and 23) induce apoptosis via both the mitochondrial and membrane death receptor pathways, involving the Bcl-2 family proteins. Taken together these results provide a role of kaurane derivatives as apoptotic inducers in tumor cells.
Asunto(s)
Apoptosis/efectos de los fármacos , Diterpenos de Tipo Kaurano/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Línea Celular Tumoral , Expresión Génica/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Ratones , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Relación Estructura-ActividadRESUMEN
The structures of the diterpenes licamichauxiioic acids A and B, isolated from Licania michauxii, which had been reported as 15-oxo-ent-kaur-9(11),16-dien-19-oic acid (1) and 15-oxo-ent-kaur-13,16-dien-19-oic acid (3), respectively, are not correct. Starting from grandiflorenic acid (6) we had prepared a compound with the proposed structure for licamichauxiioic acid A, and its spectroscopic data are different from those given for this acid. In the case of licamichauxiioic acid B, its NMR data are not in accordance with the proposed structure 3, which also violates Bredt's rule. In addition, we described a useful method for the separation of grandiflorenic and grandiflorolic acids.
Asunto(s)
Diterpenos/química , Estructura Molecular , Raíces de Plantas/químicaRESUMEN
A new lathyrane-type diterpene 8alpha,15beta-diacetoxy-7beta-benzoyloxy-3beta-(2-methylpropanoyloxy)-4alphaH,9alphaH, 11alphaH-lathyra-5E,12E-dien-14-one (latazienone) has been isolated from the latex of Euphorbia latazi Kunth. The structure of the new diterpene was determined by a combination of ID- and 2D-NMR techniques.