RESUMEN
This is the first report on a unique hybrid molecule made of estradiol and testosterone (TS). This distinctive hybrid molecule (1) was designed to interact with both the estrogen receptor (ER) and the androgen receptor (AR) found in hormone-dependent female and male cancer cells, and was synthesized using ethynylestradiol (17EE) as the estrogenic component and 7α-(4-azido-but-2-enyl)-4-androsten-17ß-ol-3-one as the androgenic counterpart in a seven-step reaction with â¼ 26 % overall yield. We reasoned that the dual receptor binding ability could allow 1 to act as an antihormone. This was tested on hormone-dependent and hormone-independent breast cancer (BCa) and prostate cancer (PCa) cells. The antiproliferative activity was also assessed on colon and skin cancer cells. We found that 1 was active against MCF7 (ER + ) BCa cells (IC50 of 4.9 µM), had lower inhibitory potency on LNCaP (AR + ) PCa cells (IC50 > 5 µM) and no effect on PC3 and DU145 (AR-) PCa cells. This suggests that the estrogenic component of 1 can interact with the ER on MCF7 cells more effectively than the androgenic component with the AR on LNCaP PCa cells, possibly due to a suboptimal spacer or linkage site(s). Nonetheless, the hybrid 1 was active against colon (HT-29) and melanoma (M21) cancer cells (IC50 of 3.5 µM and 2.3 µM, respectively), and had low cross-reactivity with the drug- and androgen-metabolizing cytochrome P450 3A4 (CYP3A4, IC50 â« 5 µM). These findings demonstrate the anticancer potential of 1 and warrant further explorations on this new type of hybrids.
Asunto(s)
Antineoplásicos , Proliferación Celular , Estradiol , Testosterona , Humanos , Testosterona/farmacología , Testosterona/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Estradiol/farmacología , Estradiol/química , Estradiol/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Relación Estructura-Actividad , Receptores de Estrógenos/metabolismo , Receptores Androgénicos/metabolismo , Estructura Molecular , MasculinoRESUMEN
Estradiol dimers (EDs) possess significant anticancer activity by targeting tubulin dynamics. In this study, we synthesised 12 EDs variants via copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction, focusing on structural modifications within the aromatic bridge connecting two estradiol moieties. In vitro testing of these EDs revealed a marked improvement in selectivity towards cancerous cells, particularly for ED1-8. The most active compounds, ED3 (IC50 = 0.38 µM in CCRF-CEM) and ED5 (IC50 = 0.71 µM in CCRF-CEM) demonstrated cytotoxic effects superior to 2-methoxyestradiol (IC50 = 1.61 µM in CCRF-CEM) and exhibited anti-angiogenic properties in an endothelial cell tube-formation model. Cell-based experiments and in vitro assays revealed that EDs interfere with mitotic spindle assembly. Additionally, we proposed an in silico model illustrating the probable binding modes of ED3 and ED5, suggesting that dimers with a simple linker and a single substituent on the aromatic central ring possess enhanced characteristics compared to more complex dimers.
Asunto(s)
Antineoplásicos , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Estradiol , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Estradiol/farmacología , Estradiol/química , Estradiol/síntesis química , Estructura Molecular , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Dimerización , Química Clic , Línea Celular TumoralRESUMEN
Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17ß-estradiol (2-ClE2) or 4-chloro-17ß-estradiol (4-ClE2) was implanted subcutaneously for 52 weeks into August Copenhagen Irish (ACI) rats, a preferred animal model for human breast cancer. 17ß-Estradiol (E2) frequently induced mammary tumors while both 2-ClE2 and 4-ClE2 did not. Their 17α-ethinyl forms, thought to be orally active estrogens, were also synthesized. Neither 2-chloro-17α-ethinylestradiol (2-ClEE2) nor 4-chloro-17α-ethinylestradiol (4-ClEE2) induced tumors. The less carcinogenic effects were supported by histological examination of mammary glands of ACI rats treated with the chlorinated estrogens. A chlorine atom positioned at the 2- or 4-position of E2 may prevent the metabolic activation, resulting in reducing the carcinogenicity. 2-ClE2 and 4-ClE2 administered subcutaneously and 2-ClEE2 and 4-ClEE2 given orally to ovariectomized rats all showed uterotrophic potency, albeit slightly weaker than that of E2. Our results indicate that less carcinogenic chlorinated estrogens retaining estrogenic potential could be safer alternatives to the carcinogenic estrogens now in use for HRT.
Asunto(s)
Carcinógenos/toxicidad , Estradiol/análogos & derivados , Terapia de Reemplazo de Estrógeno/efectos adversos , Neoplasias Mamarias Experimentales/prevención & control , Animales , Pruebas de Carcinogenicidad , Carcinógenos/síntesis química , Daño del ADN , Estradiol/síntesis química , Estradiol/toxicidad , Etinilestradiol/análogos & derivados , Etinilestradiol/síntesis química , Etinilestradiol/toxicidad , Femenino , Humanos , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/patología , Ratas , Ratas Endogámicas ACI , Útero/efectos de los fármacos , Útero/patologíaRESUMEN
A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay. The most active compounds with IC50,MCF-7 < 10 µM were also tested for cytotoxicity in vitro against MDA-MB-231 (ER-) breast adenocarcinoma cells and conditionally normal human skin fibroblasts (HSF). The patterns of structure-antitumor activity relationships of the obtained compounds were analyzed. The most active compounds were found to contain a six-membered ketal ring, a methyl group in position 5, a 3,4-dimethoxystyryl fragment in positions 2 or 6 of the pyridoxine ring, and a trans-configuration of the double bond. Using the most active compound 5a as a representative cytotoxic agent, we have demonstrated that it has high specificity and antiproliferative activity against MCF-7 (ER+) tumor cells (IC50 < 5 µM), and a higher therapeutic index compared to the reference compound raloxifene (48 versus 5.8). Compound 5a decreased the mitochondrial membrane potential and increased the level of reactive oxygen species in MCF-7 cells, but not MDA-MB-231 cells. Compound 5a did not affect the distribution of cell cycle phases and induced apoptosis in MCF-7 cells, but not MDA-MB-231. Unlike compound 5a, raloxifene decreased mitochondrial potential, increased the ROS level, and induced apoptosis in both MCF-7 and MDA-MB-231 cells, which indicated a lack of selectivity for cells with estrogen receptor expression. It was also shown that compound 5a reduced the level of ERα expression in cells to a lesser extent than raloxifene and, unlike the latter, did not activate the PI3K/Akt signaling pathway.
Asunto(s)
Antineoplásicos/farmacología , Estradiol/farmacología , Piridoxina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Estradiol/síntesis química , Estradiol/química , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Piridoxina/química , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A variety of 17α-triazolyl and 9α-cyano derivatives of estradiol were prepared and evaluated for binding to human ERß in both a TR-FRET assay, as well as ERß and ERα agonism in cell-based functional assays. 9α-Cyanoestradiol (5) was nearly equipotent as estradiol as an agonist for both ERß and ERα. The potency of the 17α-triazolylestradiol analogs is considerably more variable and depends on the nature of the 4-substituent of the triazole ring. While rigid protein docking simulations exhibited significant steric clashing, induced fit docking providing more protein flexibility revealed that the triazole linker of analogs 2d and 2e extends outside of the traditional ligand binding domain with the benzene ring located in the loop connecting helix 11 to helix 12.
Asunto(s)
Estradiol/farmacología , Receptor alfa de Estrógeno/agonistas , Receptor beta de Estrógeno/agonistas , Estrógenos/farmacología , Línea Celular , Relación Dosis-Respuesta a Droga , Estradiol/síntesis química , Estradiol/química , Estrógenos/síntesis química , Estrógenos/química , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
An efficient and concise synthesis of 2-methoxyestradiol (4) from 17ß-estradiol (1) has been achieved in three synthetic steps with a 63.3% overall yield. The key step was the palladium-catalyzed direct C(sp2)-H methoxylation of 2-aryloxypyridines. Using 2-pyridyloxyl as the directing group, Pd(OAc)2 as the catalyst, PhI(OAc)2 as the oxidant and methanol as both the methoxylation reagent and solvent, the methoxy group could be handily installed at the 2-position of 3-(2-pyridoxy) estradiol (2). Subsequently, the pyridyl group could be easily removed by nucleophilic substitution with a methoxy anion after being oxidized to a pyridyl N-oxide by m-chloroperoxybenzoic acid, delivering the target product 2-methoxyestradiol (4) in quantitative yield. In contrast, when the pyridyl directing group was removed by the TfOMe-NaOMe/MeOH system as reported in the literature, TfOMe inevitably methylated the 17-OH of 2-methoxy-3-(2-pyridoxy) estradiol (3). In effect, we have fortuitously found a new method to cleave the pyridyl directing group, which is highly suitable for substrates bearing hydroxy groups.
Asunto(s)
Carbono/química , Estradiol/química , Estradiol/síntesis química , Técnicas de Química Sintética , EstereoisomerismoRESUMEN
Steroid sulfatase (STS) is an important enzyme regulating the conversion of sulfated steroids into their active hydroxylated forms. Notably, the inhibition of STS has been shown to decrease the levels of active estrogens and was translated into clinical trials for the treatment of breast cancer. Based on quantitative structure-activity relationship (QSAR) and molecular modeling studies, we herein report the design of fluorescent inhibitors of STS by adding a dansyl group on an estrane scaffold. Synthesis of 17α-dansylaminomethyl-estradiol (7) and its sulfamoylated analog 8 were achieved from estrone in 5 and 6 steps, respectively. Inhibition assays on HEK-293 cells expressing exogenous STS revealed a high level of inhibition for compound 7 (IC50 = 69 nM), a value close to the QSAR model prediction (IC50 = 46 nM). As an irreversible inhibitor, sulfamate 8 led to an even more potent inhibition in the low nanomolar value (IC50 = 2.1 nM). In addition, we show that the potent STS inhibitor 8 can be employed as an optical imaging tool to investigate intracellular enzyme sub-localization as well as inhibitory behavior. As a result, confocal microscopy analysis confirmed good penetration of the STS fluorescent inhibitor 8 in cells and its localization in the endoplasmic reticulum where STS is localized.
Asunto(s)
Estradiol/análogos & derivados , Esteril-Sulfatasa/antagonistas & inhibidores , Estradiol/síntesis química , Estrona/química , Células HEK293 , Humanos , Microscopía Confocal , Modelos Moleculares , Estructura Molecular , Imagen Óptica , Relación Estructura-Actividad CuantitativaRESUMEN
Fifteen novel furoxan-based nitric oxide (NO) releasing hybrids of estradiol derivatives were synthesized and evaluated inâ vitro anti-proliferative activity in MDA-MB-231, A2780, Hela and HUVEC cell lines. Most of them displayed potent anti-proliferative effects. Among the compounds, 4-bromo-3-((phenylsulfonyl)-1,2,5-oxadiazole 2-oxide)-oxy-propoxy-estradiol (11 b) exhibited the best activity with IC50 values of 3.58-0.0008â µM. Preliminary pharmacological studies showed that 11 b induced apoptosis and hardly affected the cell cycle of MDA-MB-231 cell line. NO-releasing capacity and inhibition of ERK/MAPK pathway signaling might explain the potent antineoplastic activity of these compounds. The preliminary structure-activity relationship (SAR) showed that steroidal scaffolds with a linker in 3-position were favorable moieties to evidently increase the bioactivities of these hybrids. Overall, these results implied that 11 b merited to be further investigated as a promising anti-cancer candidate.
Asunto(s)
Estradiol/síntesis química , Oxadiazoles/síntesis química , Antineoplásicos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estradiol/farmacología , Humanos , Sistema de Señalización de MAP Quinasas , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Óxido Nítrico/química , Óxido Nítrico/farmacología , Oxadiazoles/farmacología , Esteroides/química , Relación Estructura-ActividadRESUMEN
Estrogen receptors are overexpressed in 70% of breast cancer and identification of their presence is important to select the appropriate treatment. This work proposes the preparation and evaluation of an estradiol derived as potential ER imaging agent. Ethinylestradiol was derivatized to introduce a dithiocarbamate function for Tc coordination. Labeling was achieved through the formation of a symmetric Tc(V)-nitrido complex with a radiochemical purity (RCP) > 95%. Physicochemical evaluation, cell uptake, biodistribution in normal animals and in nude mice bearing induced ER + breast tumors showed promising results.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Compuestos de Organotecnecio , Radiofármacos , Animales , Neoplasias de la Mama/metabolismo , Estabilidad de Medicamentos , Estradiol/análogos & derivados , Estradiol/síntesis química , Estradiol/química , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Compuestos de Organotecnecio/síntesis química , Compuestos de Organotecnecio/química , Compuestos de Organotecnecio/farmacocinética , Unión Proteica , Radiofármacos/síntesis química , Radiofármacos/química , Radiofármacos/farmacocinética , Ratas , Ratas Wistar , Receptores de Estrógenos/metabolismo , Distribución TisularRESUMEN
To prepare new type of estrane hybrid molecules, we chose 3-methoxy- and 3-benzyloxy-17ß,16ß-epoxymethylene-estra-1,3,5(10)-trienes as starting materials (2 and 5). These steroid oxetanes were transformed with ethylene glycol in the presence of BF3.OEt2 into 3-methoxy- and 3-benzyloxy-16ß-(2'-oxa-4'-hydroxy)butyl-17ß-hydroxy-estra-1,3,5(10)-trien-17ß-ols (3a and 6a). Iodination of the terminal hydroxy group afforded iodo derivatives 3b and 6b, which underwent one-pot 3-O-alkylation with unprotected ascorbic acid to yield 3c and 6c. The same process with salicylic acid led to 2-O-alkylated salicylic acid derivatives 3d and 6d. Iodo derivatives 3b and 6b underwent nucleophilic exchange reaction with NaN3 furnishing the corresponding azido compounds 3e and 6e. These compounds were subjected to azide-alkyne CuAAC reactions with phenylacetylene and their p-substituted derivatives to form 1,4-substituted triazoles 3f-h and 6f-h. The reduction of 3e and 6e with hydrazine hydrate in the presence of Raney Ni provided the corresponding amino derivatives 3i and 6i. These compounds were reacted further with varied substituted benzoic acids to deliver terminal benzamido derivatives 3j-m and 6j-m. We determined the in vitro antiproliferative activities of compounds 2, 5, 3a-m and 6a-m by means of MTT assays on a panel of human adherent cancer cell lines A2780, MCF-7, MB-231 and SiHa.
Asunto(s)
Antineoplásicos/farmacología , Estradiol/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Estradiol/síntesis química , Estradiol/química , Humanos , Células MCF-7 , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series consisting of substituted benzoylbenzamide derivatives of 17α-E-vinyl estradiol 6a-i and 7a-d was prepared in good overall yields from the corresponding novel iodinated benzoylbenzamide precursors using Pd(0)-catalyzed Stille coupling. Biological evaluation using competitive binding assays indicated that all compounds were effective ligands for the ERα- and ERß-LBD (RBAâ¯=â¯0.5-10.0% of estradiol). Most of the compounds expressed lower stimulatory (agonist) potency (RSA <0.2-0.5%) compared to their binding affinity, however, the meta-substituted isomer 6h demonstrated a level of efficacy (RSAâ¯=â¯5.7%) comparable to its affinity (RBAâ¯=â¯9.5%). Docking studies of 6b, 6h, and 6i with the 2YAT crystal structure suggested that higher affinity and efficacy of 6h are due to an effective set of interactions with exposed receptor sidechains not observed with the ortho- and para- isomers. In this binding model, the terminal ring of the ligand is exposed to the solvent space, which would explain both the small variation in RBA values and the narrow SAR for the diverse structural features.
Asunto(s)
Benzamidas/química , Estradiol/síntesis química , Estradiol/metabolismo , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/metabolismo , Unión Competitiva , Técnicas de Química Sintética , Estradiol/química , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Dominios ProteicosRESUMEN
Molecular imaging of estrogen receptor-positive (ER+) pathway-activated system serves the basis of ER+ disease management such as cancers and endometriosis. ER+ patients have better response to endocrine therapy and survive twice as long as negative ER patients. However, tumor resistance resulting from clinical used aromatase inhibitors and antiestrogens is unpredictable. Radiolabeled ER+ ligand could quantify ER+ tissue uptake which helps to stage and restage of the cancer as well as endometriosis. The differential diagnosis of ER+ lesions by using a labeled ligand helps to select the patients for optimal response to endocrine therapy and to discontinue the treatment when resistance occurs. In addition, radiolabeled ER+ ligand serves as basis for image-guided response follow-up. Glutamate receptors are cell surface receptors which are overexpressed in inflammation and infection. Using glutamate peptide as a drug carrier helps to target intracellular genes via glutamate receptor-mediated process. Reports have shown that polyglutamate is a drug carrier that could alter drug solubility and enhance estrogen receptor-ligand binding pocket. However, polyglutamate was a blend of mixed polymer with a wide range of molecular weight. Thus, the structural confirmation and purity of the conjugates were not optimized. To overcome this problem, the efficient synthesis of glutamate peptide-estradiol (GAP-EDL) conjugate was achieved with high purity. EDL was conjugated site-specific at the first glutamate of GAP. The average cell uptake of 68Ga-GAP-EDL was 5-fold higher than the previous reported synthesis. The efficient synthesis of GAP-EDL has greatly enhanced sensitivity and specificity in cell uptake studies. In vivo PET imaging studies indicated that 68Ga-GAP-EDL could image ER (+) tumors in MCF-7 tumor-bearing mice. Therefore, GAP-EDL makes it possible to image ER-enriched endometriosis and cancer.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Estradiol , Radioisótopos de Galio , Marcaje Isotópico , Péptidos , Tomografía de Emisión de Positrones , Neoplasias de la Mama/metabolismo , Estradiol/síntesis química , Estradiol/química , Estradiol/farmacología , Femenino , Radioisótopos de Galio/química , Radioisótopos de Galio/farmacología , Humanos , Células MCF-7 , Péptidos/síntesis química , Péptidos/química , Péptidos/farmacologíaRESUMEN
[18F]fluoroestradiol ([18F]FES) is well-established PET radiotracer for diagnosing and monitoring treatment of estrogen-positive breast cancer. The radiotracer is produced via one-pot two steps synthesis using cyclic sulfate precursor and is usually purified by semi-preparative HPLC. Here we suggested simple SPE purification procedure using OASIS WAX 3cc and Sep-Pak QMA light cartridges that afforded [18F]FES in typically 15% RCY (corrected for decay) within 45â¯min formulated in 5% EtOH/saline. All purity parameters were well within specifications recommended in the Investigator's Brochure for [18F]Fluoroestradiol.
Asunto(s)
Estradiol/análogos & derivados , Radioisótopos de Flúor/aislamiento & purificación , Radiofármacos/síntesis química , Extracción en Fase Sólida/métodos , Automatización , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/metabolismo , Cromatografía Líquida de Alta Presión , Estradiol/síntesis química , Estradiol/aislamiento & purificación , Femenino , Humanos , Tomografía de Emisión de Positrones , Radiofármacos/aislamiento & purificación , Receptores de Estrógenos/metabolismo , Extracción en Fase Sólida/instrumentaciónRESUMEN
INTRODUCTION: A novel radiotracer 1(2(2(2[18F]fluoroethoxy)ethoxy)ethyl)1H1,2,3triazoleestradiol ([18F]FETE) was successfully synthesized, characterized and evaluated in mice for estrogen receptor (ER)-positive breast cancer targeting with positron emission tomography (PET) imaging. METHODS: The tosylate precursor 3 was radiolabeled with 18F and then reacted with 17αethinylestradiol to produce the final [18F]FETE. The physicochemical properties of [18F]FETE were tested in vitro, including determination of the octanol/water partition coefficient, stability and cellular uptake in MCF-7 (ER-positive) and MDA-MB-231 (ER-negative) cells. An ex vivo biodistribution study was performed in normal Sprague Dawley rats, and in vivo microPET imaging was performed on MCF-7 and MDA-MB-231 tumor-bearing mice. The results of biodistribution and PET imaging of [18F]FETE were compared with that of known 16α[18F]fuoro17ßestradiol ([18F]FES). Radiation dose estimates for [18F]FETE were also analyzed. RESULTS: [18F]FETE was obtained in high radiochemical yield (46.59⯱â¯8.06%) with high radiochemical purity (>99%) after HPLC purification and high molar activity (15.45⯱â¯3.15â¯GBq/µmol). [18F]FETE is a moderate lipophilic compound with good in vitro stability and the total synthesis time was 55 to 65â¯min. In biodistribution studies, [18F]FETE showed high uptake in the ER-abundant uterine tissue of normal immature SD rats (8.55⯱â¯1.21 and 6.83⯱â¯1.70%ID/g at 1â¯h after intravenous and intraperitoneal injection, respectively), and could be blocked with estradiol effectively (the uterus uptake was decreased to 0.63⯱â¯0.35%ID/g at 1â¯h after iv injection). MicroPET imaging of tumor-bearing mice with [18F]FETE at 1â¯h after iv injection revealed considerable uptake in ER-positive MCF-7 tumors (4.63⯱â¯0.73%ID/g) that could be inhibited (1.47⯱â¯0.29%ID/g) and low uptake in ER-negative MDA-MB-231 tumors (1.97⯱â¯0.36%ID/g). [18F]FES has relatively low uptake in ER-positive tumor (0.24⯱â¯0.19%ID/g) when compared with [18F]FETE. The adult female effective radiation dose of [18F]FETE in mice was estimated as 0.0022â¯mSv/MBq. CONCLUSIONS: A novel 17αethinylestradiol-based ER probe [18F]FETE was developed with high molar activity and good in vitro stability. Based on the results of bio-evaluation in normal immature rats and tumor-bearing mice, it might be a promising candidate for specific PET imaging of ER-positive breast cancer.
Asunto(s)
Estradiol/química , Regulación Neoplásica de la Expresión Génica , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Neoplasias Mamarias Experimentales/metabolismo , Tomografía de Emisión de Positrones/métodos , Receptores de Estrógenos/metabolismo , Animales , Estradiol/análogos & derivados , Estradiol/síntesis química , Estradiol/metabolismo , Estradiol/farmacocinética , Femenino , Humanos , Células MCF-7 , Ratones , Radioquímica , Radiometría , Distribución TisularRESUMEN
BF3·Et2O-catalyzed aldol condensation of steroid sapogenins with 2-formyl-estradiol diacetate afforded two novel classes of steroid dimers in which an estrogenic core is attached to the spirostanic side chain of an steroid sapogenin through an exocyclic double bond in position C-23, or through a spiro centre in C-22.
Asunto(s)
Aldehídos/química , Estradiol/síntesis química , Sapogeninas/química , Esteroides/química , Aldehídos/síntesis química , Benzaldehídos/síntesis química , Benzaldehídos/química , Catálisis , Estradiol/análogos & derivados , Estradiol/química , Espectroscopía de Resonancia Magnética , Sapogeninas/síntesis química , Estereoisomerismo , Esteroides/síntesis químicaRESUMEN
A series of 17ß-amide-2-methoxyestradiol compounds were synthesized with an aim to enhance the antiproliferative effect of 2-methoxyestradiol. The antiproliferative activity of 2-methoxyestradiol analogs against human cancer cells was investigated. 2-methoxy-3-benzyloxy-17ß-chloroacetamide-1,3,5(10)-triene (5e) and 2-methoxy-3-hydroxy-17ß-butyramide-1,3,5(10)-triene (6c) had comparable or better antitumor activity than 2-methoxyestradiol. The elimination half-life of 6c (t1/2ß=240.93min) is ten times longer than 2-ME and the area under the curve was seven times (AUC0-tmin=2068.20±315.74µgmL-1min) higher than 2-ME, respectively. Whereas 5e had similar pharmacokinetic behavior with 2-ME (t1/2ß=22.28min) with a t1/2ß of 29.5 min. 6c had higher blood concentration, longer actuation duration and better suppression rate against S180 mouse ascites tumor than 2-methoxyestradiol.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Estradiol/análogos & derivados , Neoplasias/tratamiento farmacológico , 2-Metoxiestradiol , Animales , Diseño de Fármacos , Estradiol/administración & dosificación , Estradiol/síntesis química , Estradiol/química , Estradiol/farmacocinética , Humanos , Células MCF-7 , RatonesRESUMEN
2-methoxyestradiol is a novel agent showing both anti-angiogenic and vascular disrupting properties. In this study, a series of 11α-substituted 2-methoxyestradiol analogs have been designed and synthesized targeting dual ERα and microtubulin. Biological evaluation was performed on their anti-proliferative activities against 5 different cell lines. The results indicated that most compounds exhibited good activities, in which compound 24c and 30c showed the best activity with low micromolar IC50 (2.73 µM -7.75 µM) in all cell lines. The investigation of ER affinity showed that the majority of the compounds displayed good activity at the concentration of 50 µM. In further mechanism study, it was observed that 24c and 30c could induce G2/M cell cycle arrest as well as significant anti-estrogenic activity. In CAM assay, compound 24c and 30c presented significantly anti-angiogenesis activity comparable with 2-methoxyestradiol. Overall, based on biological activities data, 24c and 30c can be identified as a potential lead molecule which might be of therapeutic importance for cancer treatment.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Diseño de Fármacos , Estradiol/análogos & derivados , Moduladores de los Receptores de Estrógeno/farmacología , 2-Metoxiestradiol , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Pollos , Membrana Corioalantoides/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estradiol/síntesis química , Estradiol/química , Estradiol/farmacología , Moduladores de los Receptores de Estrógeno/síntesis química , Moduladores de los Receptores de Estrógeno/química , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Células MCF-7 , Estructura Molecular , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Relación Estructura-ActividadRESUMEN
Enantioselective total synthesis of estradiol methyl ether has been accomplished in a pot-economical manner using five reaction vessels and four purifications. The key reaction is a diphenylprolinol silyl ether mediated domino Michael/aldol reaction to afford bicyclo[4.3.0]nonane derivatives, containing the A, C, and D rings of steroids, as a single isomer with excellent enantioselectivity. Six reactions such as oxidation, hydrogenation, formation of acid chloride, Friedel-Crafts reaction, deprotection, and reduction can be carried out in the last one-pot sequence.
Asunto(s)
Estradiol/síntesis química , Éteres/química , Compuestos Orgánicos/química , Catálisis , Análisis Costo-Beneficio , Estradiol/química , Modelos MolecularesRESUMEN
Estrogen deprivation is associated with delayed healing, while estrogen replacement therapy (ERT) accelerates acute wound healing and protects against development of chronic wounds. However, current estrogenic molecules have undesired systemic effects, thus the aim of our studies is to generate new molecules for topic administration that are devoid of systemic effects. Following a preliminary study, the new 17ß-estradiol derivatives 1 were synthesized. The estrogenic activity of these novel compounds was evaluated in vitro using the cell line ERE-Luc B17 stably transfected with an ERE-Luc reporter. Among the 17ß-estradiol derivatives synthesized, compounds 1e and 1f showed the highest transactivation potency and were therefore selected for the study of their systemic estrogenic activity. The study of these compounds in the ERE-Luc mouse model demonstrated that both compounds lack systemic effects when administered in the wound area. Furthermore, wound-healing experiments showed that 1e displays a significant regenerative and anti-inflammatory activity. It is therefore confirmed that this class of compounds are suitable for topical administration and have a clear beneficial effect on wound healing.
Asunto(s)
Estradiol/administración & dosificación , Terapia de Reemplazo de Estrógeno , Piel/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Administración Tópica , Animales , Células Cultivadas , Estradiol/análogos & derivados , Estradiol/síntesis química , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Estrógenos/metabolismo , Estrona/metabolismo , Femenino , Humanos , Ratones , Ovariectomía , Piel/lesiones , Piel/patología , Cicatrización de Heridas/fisiologíaRESUMEN
Micro-particles of 17ß-estradiol (ED) were prepared with polyvinylpyrrolidone (PVP) by in situ pH-dependent solubility technique. Products were characterized using multiple instruments, and molecular interactions between ED and PVP were explored. Powder X-ray diffraction and thermal analysis revealed crystalline ED in the micro-particles is hemihydrated. PVP was also present in the micro-particles. Laser particle size analysis and scanning electron microscopy revealed thin slice morphology, which might have resulted from the influence of PVP. Moreover, the results of contact angle, specific surface area, and dynamic vapor sorption showed that the surface properties of products were improved. These physicochemical properties of the micro-particles resulted in an obvious improvement in dissolution rate. Fourier transform infrared spectroscopy and 1H nuclear magnetic resonance revealed hydrogen bonding between ED and PVP. A method was established for the preparation of micro-particles through the addition of PVP during the reaction process.