Synthesis and biological evaluation of salpichrolide analogs as antiestrogenic agents.

The antiestrogenic activity of three natural salpichrolides A, G and B (1, 3 and 4) and of five synthetic analogs containing an aromatic D ring and a simplified side chain (5-9), was evaluated on MCF-7 cells. The 2,3-ene-1-keto steroids 8 and 9 were obtained from 3ß-acetoxy-17(13→18)-abeo-5αH-pregna-13,15,17-trien-20-one, the key step for these syntheses being a Wharton carbonyl rearrangement of a 1,2-epoxy-3-keto steroid to the allylic alcohol using hydrazine hydrate. The antiestrogenic activity was evaluated by performing dose-response experiments in ER(+) MCF-7 breast cancer cells. Dose-dependent proliferation was quantified via [(3)H]-thymidine incorporation after 3 days treatment. Salpichrolides A, G and B and analogs 5, 8 and 9 were active as antiestrogens with compound 9 being the most active of the synthetic analogs. Compounds 5 and 9 were also evaluated against the ER(-) cell line MDA-MB-231 and shown to be inactive.

Efecto de la combinación de dieta hiperlipídica y la privación de estrógeno sobre la integridad ósea bucal de ratas / Effect of association high fat diet: hypoestrogenism on bone integrity: of oral rats

El objetivo de este estudio fue evaluar el efecto de la deficiencia de estrógenos asociada con dieta hiperlipídica sobre la integridad de la mandíbula de ratas. Para este experimento se selecionaron Ratas Wistar fueron divididas en 4 grupos: Control (C4%), Control hiperlipídica19% (C19%), ovariectomizadas 4% (OVX4%) y Ovariectomizada 19% (OVX19%). El experimento empezó con la castración (90 días), seguida de dieta hiperlipídica durante 30 días. Al fin, la sangre fue recogida para el análisis de los niveles séricos de calcio, fósforo, fosfatasa alcalina y estradiol. El fósforo disminuyó cuando hay aumento de la fosfatasa alcalina en todos los grupos en comparación con el C4%. En las vértebras L4, los pesos inmersos y húmedos aumentarán con la castración y la dieta hiperlipídica, mientras que el porcentaje de materia orgánica y minerales disminuyeron. En las mandíbulas, los pesos inmersos, húmedos y la densidad ósea aumentaran con la castración, pero disminuyeron con la combinación de castración / dieta. En las cenizas de las mandíbulas, el porcentaje de magnesio aumentó significativamente en todos los grupos. En las pruebas biomecánicas de las vértebras L4 y fémur no se encontraron diferencias significativas entre los grupos. Sin embargo, los grupos alimentados con dieta hiperlipídica tuvieron una menor resistencia a la tensión aplicada en la mandíbula. Dentro de las limitaciones del estudio, se puede notar que en estas ratas, la deficiencia de esteroides sexuales asociada con la dieta hiperlipídica influye negativamente sobre la integridad del hueso mandibular...

The aim of this study was to evaluate the effect of estrogen deficiency associated with a high fat diet on bone integrity of the jaw of rats. The pregnant rats were evaluated by vaginal cytology were 90 days old, divided into four groups: Control (C4%), Control hiperlipídica19% (C19%), ovariectomized 4% (OVX4%) and Ovariectomized19% (OVX19%). The experiment began with castration (90 days), followed by feeding with a high fat diet for 30 days. At the end, blood was collected. Jaws, vertebrae L4 and femur were removed and prepared for analysis. There were no differences in food intake, the body length or in bone measurements. Serum calcium decreased in the castrated groups. The level of phosphorus decreased and alkaline phosphatase increased in all groups. Some differences were observed among physical parameters. L4 vertebrae, immersed and wet weights increased with castration and the high fat diet, while the percentage of organic material and mineral decreased. In the jaws, immersed and wet weights and bone density increased with castration, but decreased with the combination spaying/fat diet. Bone volume and percentage of water decreased with intake of high fat diet. In the ashes of the jaws percentages of magnesium were increased in all groups, without changes in calcium and phosphorus. Groups fed with high-fat diets had lower resistance to the applied voltage in the jaw. It was demonstrated in these rats that, the deficiency of sex steroids associated with a high fat diet negatively influences mandibular bone integrity...

Evaluation of estrogenic, antiestrogenic and genotoxic activity of nemorosone, the major compound found in brown Cuban propolis.

BACKGROUND: Brown propolis is the major type of propolis found in Cuba; its principal component is nemorosone, the major constituent of Clusia rosea floral resins. Nemorosone has received increasing attention due to its strong in vitro anti-cancer action. The citotoxicity of nemorosone in several human cancer cell lines has been reported and correlated to the direct action it has on the estrogen receptor (ER). Breast cancer can be treated with agents that target estrogen-mediated signaling, such as antiestrogens. Phytoestrogen can mimic or modulate the actions of endogenous estrogens and the treatment of breast cancer with phytoestrogens may be a valid strategy, since they have shown anti-cancer activity. METHODS: The aim of the present investigation was to assess the capacity of nemorosone to interact with ERs, by Recombinant Yeast Assay (RYA) and E-screen assays, and to determine by comet assay, if the compound causes DNA-damaging in tumoral and non-tumoral breast cells. RESULTS: Nemorosone did not present estrogenic activity, however, it inhibited the 17-ß-estradiol (E2) action when either of both methods was used, showing their antiestrogenicity. The DNA damage induced by the benzophenone in cancer and normal breast cells presented negative results. CONCLUSION: These findings suggest that nemorosone may have therapeutic application in the treatment of breast cancer.

Isolation and structure elucidation of an isoflavone and a sesterterpenoic acid from Henriettella fascicularis.

A new isoflavone, 4',5,7-trihydroxy-6,8-dimethylisoflavone (1), and a new sesterterpenoic acid (2), together with five known compounds, lichexanthone (3), (-)-pinoresinol (4), betulinic acid, palmitic acid, and beta-sitosterol, were isolated from a dichloromethane extract of the branches of Henriettella fascicularis. Their structures were established by extensive spectroscopic methods. An attempt to determine the absolute stereochemistry of (2E,6S)-6-[(1R,5Z,3aS,9R,10Z,12aR)-1,2,3,3a,4,7,8,9,12,12a-decahydro-9-hydroxy-3a,6,10-trimethylcyclopentanocycloundecen-1-yl]-2-methylhept-2-enoic acid (2) was performed by single-crystal X-ray analysis, using Cu Kalpha radiation. Compound 1 showed significant competitive binding to estrogen receptor beta and moderate antiestrogenic activity with cultured Ishikawa cells.

Antiestrógenos: mecanismo de acción y aplicaciones clínicas / Antiestrogens: Mechanism of action and clinical applications

Los antiestrógenos son compuestos que antagonizan la acción de los estrógenos compitiendo por su receptor. Los estrógenos están implicados en la proliferación y diferenciación de las células blanco y se consideran entre los principales factores de riesgo para el desarrollo de cáncer de mama y útero. Algunos antiestrógenos, entre ellos el Tamoxifén, son utilizados como terapia coadyuvante en el tratamiento del cáncer de mama y se ha propuesto su inclusión en los programas de prevención, en mujeres con alto riesgo. Los antiestrógenos se clasifican en tipo I o parciales (agonista/antagonista), y tipo II o puros (antagonista puro), los cuales tienen mecanismos de acción diferentes. Debido al continuo avance en el desarrollo de nuevos compuestos con actividad antiestrogénica, y su importancia aplicativa en clínica. En este documento se presenta una revisión del estado actual del conocimiento de estos compuestos, su mecanismo de acción y su aplicación clínica. El texto completo en inglés de este artículo está disponible en: http://www.insp.mx/salud/index.html

1-(2-[4-[6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiol-3-ylcarbonyl]phenoxy]ethyl)piperidinium chloride.

The title compound, raloxifene hydrochloride, C(28)H(28)NO(4)S(+).-Cl(-), belongs to the benzothiophene class of antiosteoporotic drugs. In the molecular cation, the 2-phenol ring sustains a dihedral angle of 45.3 (1) degrees relative to the benzo[b]thiophene system. The benzo[b]thiophene and phenyl ring planes are twisted with respect to the carbonyl plane, with the smallest twist component occurring between the phenyl and carbonyl planes. The N atom bears the positive charge in the molecular cation and the piperidine ring adopts an almost perfect chair conformation. The Cl(-) anion is involved in the formation of N-H...Cl and O-H...Cl intermolecular hydrogen bonds, which lead to the formation of a layer of molecular cations.