RESUMEN
17Beta-hydroxysteroid dehydrogenase Type 1 (17beta-HSD1) has a pivotal role in regulating the synthesis of oestradiol (E2) within breast tumours. In whole body studies in postmenopausal women with breast cancer the conversion of oestrone (E1) to E2 (4.4+/-1.1%) was much lower than the inactivation of E2 to E1 (17.3+/-5.0%). In contrast, an examination of in vivo oestrogen metabolism within breast tumours revealed that whereas little metabolism of E2 occurred, E1 was converted to E2 to a much greater extent in malignant (48+/-14%) than in normal (19+/-6%) breast tissue. Findings from these studies originally suggested that oestrogen metabolism within breast tumours may differ from the mainly oxidative direction found in most other body tissues and that the activity of 17beta-HSD1 might be regulated by tumour-derived factors. Several growth factors (e.g. IGF-I, IGF-II) and cytokines (e.g. IL-6, TNFalpha) have now been identified which can markedly stimulate the activity of 17beta-HSD1 and such a mechanism may account for the high concentrations of E2 found in most breast tumours. Cells of the immune system, which can infiltrate breast tumours, are thought to be a major source of the growth factors and cytokines which can modulate 17beta-HSD1 activity. Given the central role that 17beta-HSD1 has in regulating breast tumour E2 concentrations the development of potent inhibitors of this enzyme has recently attracted considerable attention. Our initial studies in this area explored the use of derivatives of E1 as inhibitors, with 2-ethyl- and 2-methoxy E1 being found to inhibit 17beta-HSD1 activity in T-47D breast cancer cells by 96+/-2 and 91+/-1% respectively at 10 microM, but with a lack of specificity. Using the E1 scaffold a number of potent, selective 17beta-HSD1 inhibitors have now been identified including E1- and 2-ethyl-E1 containing a side chain with a m-pyridylmethylamidomethyl functionality extending from the 16beta position of the steroid nucleus. At 10 microM these compounds both inhibited 17beta-HSD1 activity by >90%, however some inhibition of 17beta-HSD2 activity was exhibited by the E1 derivative (25%) but not the 2-ethyl analogue. It is now apparent that 17beta-HSD1 activity contributes to the high E2 concentrations found in most breast tumours. The identification of potent, selective novel 17beta-HSD1 inhibitors will allow their efficacy to be tested in in vitro and in vivo studies.
Asunto(s)
Neoplasias de la Mama/enzimología , Inhibidores Enzimáticos/química , Estradiol Deshidrogenasas/antagonistas & inhibidores , Estradiol Deshidrogenasas/metabolismo , Estradiol/análogos & derivados , Estrona/análogos & derivados , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Estradiol/química , Estradiol/metabolismo , Estrona/química , Estrona/metabolismo , Femenino , Humanos , Células Tumorales CultivadasRESUMEN
Carbonic anhydrases (CAs) are expressed by many solid tumours where they may act to confer a growth advantage on malignant tissues. In this study we have examined the ability of a series of steroidal and non-steroidal sulphamates (originally developed as steroid sulphatase inhibitors) and related compounds to inhibit human CAII (hCAII) activity in vitro. Using a 96-well plate assay, oestrone-3-O-sulphamate (EMATE) and two coumarin-based sulphamate drugs (667 COUMATE and STX 118) were found to have IC(50) values of 25-59 nM for the inhibition of hCAII activity. These compounds therefore have a similar CAII inhibitory potency to that of acetazolamide (IC(50)=25 nM), a known hCAII inhibitor. Docking studies have been performed with selected compounds to the crystal structure of hCAII and excellent correlation of scores with biological activity was observed. This agrees with our recent observations when we were the first to report the inhibition of hCAII by STS inhibitors. These studies and initial results with docking to the crystal structure of the extracellular domain of hCAXII indicate that the STS sulphamate ester inhibitors should also be interesting candidates to pursue as inhibitors of CA isozymes that are over-expressed in human tumours.
Asunto(s)
Antineoplásicos/farmacología , Anhidrasa Carbónica II/metabolismo , Inhibidores de Anhidrasa Carbónica/farmacología , Estrona/análogos & derivados , Esteroides/farmacología , Sulfonamidas/farmacología , Antineoplásicos/química , Sitios de Unión , Anhidrasa Carbónica II/química , Inhibidores de Anhidrasa Carbónica/química , Estrona/química , Estrona/metabolismo , Estrona/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Esteroides/química , Sulfonamidas/químicaRESUMEN
The synthesis and biological activity of a new series of benzamides and related compounds that upregulate the expression of the low-density lipoprotein (LDL) receptor in human hepatocytes (HepG2 cells) by a novel mechanism are described. The lead compound, N-[5-[(3-cyclohexylpropionyl)amino]-2-methylphenyl]-4-hydroxybe nzamide (1, RPR102359), increased the expression of the LDL receptors in HepG2 cells by 80% when tested at a concentration of 3 microM. Mevinolin (lovastatin) was found to increase the LDL receptor expression by 70% at the same concentration. In contrast to mevinolin, 1 was found to have no effect on cholesterol biosynthesis in liver homogenates or in HepG2 cells at doses where substantial upregulation of the LDL receptor was observed and thus stimulated LDL receptor expression by a novel mechanism.
Asunto(s)
Benzamidas/síntesis química , Benzamidas/farmacología , Hígado/metabolismo , Parabenos/síntesis química , Parabenos/farmacología , Fenilendiaminas/síntesis química , Fenilendiaminas/farmacología , Receptores de LDL/biosíntesis , Transcripción Genética/efectos de los fármacos , Benzamidas/química , Carcinoma Hepatocelular , Línea Celular , Colesterol/biosíntesis , Humanos , Indicadores y Reactivos , Hígado/efectos de los fármacos , Neoplasias Hepáticas , Lovastatina/farmacología , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Parabenos/química , Fenilendiaminas/química , Relación Estructura-Actividad , Células Tumorales Cultivadas , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The syntheses and biological activities of a number of benzamide derivatives, designed from rolipram, which are selective inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), are described. The effects of changes to the alkoxy groups, amide linkage, and benzamide N-phenyl ring on the inhibition of the cytosolic PDE IV from pig aorta have been investigated. As a result, some highly potent and selective PDE IV inhibitors have been identified. The most potent compounds have been further evaluated for their inhibitory potencies against PDE IV obtained from and superoxide O2- generation from guinea pig eosinophils in vitro. Selected compounds have also been examined for their activities in inhibiting histamine-induced bronchospasm in anaesthetized guinea pigs. 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide (15j) showed exceptional potency in all tests and may have therapeutic potential in the treatment of asthma.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Asma/tratamiento farmacológico , Benzamidas/síntesis química , Inhibidores de Fosfodiesterasa/síntesis química , Piridinas/síntesis química , Animales , Aorta/enzimología , Benzamidas/farmacología , Benzamidas/uso terapéutico , Espasmo Bronquial/inducido químicamente , Espasmo Bronquial/tratamiento farmacológico , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Cobayas , Histamina/farmacología , Isoenzimas/antagonistas & inhibidores , Cinética , Masculino , Estructura Molecular , Inhibidores de Fosfodiesterasa/farmacología , Piridinas/farmacología , Piridinas/uso terapéutico , Relación Estructura-Actividad , Superóxidos/metabolismo , PorcinosRESUMEN
The syntheses and biological activities of (+/-)-2-(cyanomethylene)-1-pyridin-3-ylcyclohexanecarbothioic++ + acid methylamide (6) and trans-(+/-)-2-(cyanomethyl)-1-pyridin-3-ylcyclohexanecarbothioic acid methylamide (14) derived from (+/-)-2-oxo-1-pyridin-3-ylcyclohexanecarbothioic acid methylamide (4) are reported. Compounds were tested for antagonism of potassium-induced contraction of de-endothelialized rat aorta. The effects of modification of 6 and 14 on in vitro K(+)-channel opening activity are presented. These new series of potassium channel openers so derived are best exemplified by (+/-)-2-[2-(phenylsulfanyl)ethylidene]-1-pyridin-3-ylcyclohexan ecarbothioic acid methylamide (13d, RP 66266) and trans-(+/-)-2-[2-[(phenylsulfonyl)amino]ethyl]-1-pyridin-3- ylcyclohexanecarbothioic acid methylamide (25a, RP 66784), which have IC90 values of 3 and 0.3 nM, respectively. The potency of the most active compounds indicates a possible interaction at an extra binding site. The compounds described herein are potential antihypertensive and antianginal agents.
Asunto(s)
Ciclohexanos/síntesis química , Canales de Potasio/efectos de los fármacos , Piridinas/síntesis química , Animales , Ciclohexanos/farmacología , Técnicas In Vitro , Masculino , Conformación Molecular , Picolinas/farmacología , Piranos/farmacología , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Vasodilatadores/síntesis química , Vasodilatadores/farmacologíaRESUMEN
Evidence is presented which supports the postulate that the photobilirubins IIA and IIB are diastereoisomers in which the C-3 vinyl group has cyclized intramolecularly. The evidence comes principally from proton n.m.r. spectroscopy at 400 MHz and from chemical considerations. The cyclic structures require the E-configuration at the C-4 double bond in the precursor; this is the first structural evidence for the Z leads to E isomerization in bilirubin and supports the view that the precursor (photobilirubin IA or IB) is (4E, 15Z)-bilirubin. Brief irradiation of photobilirubin II gives bilirubin, a new compound (photobilirubin III) and unchanged starting material. The various photoisomers are discussed in terms of their inter-relationships and biological fates.