RESUMEN
The first 1,3-dipolar cycloaddition of 2H-azirines with nitrones, a straightforward approach toward the regioselective synthesis of 1,2,4,5-tetrasubstituted imidazoles, is reported. This trifluoroacetic acid-catalyzed protocol tolerates a broad range of aliphatic and aromatic substrates, offering an efficient access to highly diverse, multisubstituted imidazoles in isolated yields up to 83% under mild conditions.
RESUMEN
A regio- and diastereoselective 1,3-dipolar cycloaddition of 2 H-azirines with azomethine ylides generated in situ from isatins and α-amino acids has been elaborated, affording an unprecedented aziridine-fused spiro[imidazolidine-4,3'-oxindole] framework. This one-pot three-component reaction tolerates a wide range of substrates and enables the construction of highly diverse 1,3-diazaspiro[bicyclo[3.1.0]hexane]oxindoles in isolated yields up to 81% under mild conditions.
RESUMEN
17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) is a key enzyme in the biosynthesis of 17ß-estradiol. Novel estrone-based compounds bearing various 15ß-oxa-linked substituents and hydroxy, methoxy, benzyloxy, and sulfamate groups in position C3 as potential 17ß-HSD1 inhibitors have been synthesized. In addition, in vitro inhibitory potentials measured in the presence of excess amount of NADPH or NADH were investigated. We observed substantial inhibitory potentials for several derivatives (IC50 < 1 µM) and increased binding affinities compared to unsubstituted core molecules. Binding and inhibition were found to be cofactor-dependent for some of the compounds and we propose structural explanations for this phenomenon. Our results may contribute to the development of new 17ß-HSD1 inhibitors, potential drug candidates for antiestrogen therapy of hormone-dependent gynecological cancers.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Estrona/farmacología , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estrona/síntesis química , Estrona/química , Humanos , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Microwave-assisted syntheses of novel ring d-condensed 2-pyrazolines in the estrone series were efficiently carried out from steroidal ,-enones and hydrazine derivatives. The ring-closure reaction of 16-benzylidene estrone 3-methyl ether with hydrazine in acetic acid resulted in a 2:1 diastereomeric mixture of two 16,17-cis fused pyrazolines, which is contrary to the former literature data for both stereoselectivity and product structure. However, the cyclization reactions of a mestranol-derived unsaturated ketone with different arylhydrazines in acidic ethanol furnished the heterocyclic products in good to excellent yields independently of the substituents present on the aromatic ring of the reagents applied. The MW conditions also permitted the ring-closure reaction with p-nitrophenylhydrazine which is unfavorable under conventional heating. Moreover, the transformations led to the heterocyclic compounds stereoselectively with a 16,17-cis ring junction without being susceptible to spontaneous and promoted oxidation to pyrazoles.
Asunto(s)
Estrona/química , Microondas , Pirazoles/química , Estereoisomerismo , Ciclización , Modelos Moleculares , Estructura MolecularRESUMEN
A ZnCl2-catalyzed diastereoselective Joullié-Ugi three-component reaction from 2 H-azirines, isocyanides, and carboxylic acids was established. The protocol allows the preparation of highly and diversely functionalized N-acylaziridine-2-carboxamide derivatives in up to 82% isolated yields. Moreover, the applicability of N-acylaziridines is demonstrated through a variety of transformations.
RESUMEN
A sequential one-pot approach towards N,N'-disubstituted guanidines from N-chlorophthalimide, isocyanides and amines is reported. This strategy provides straightforward and efficient access to diverse guanidines in yields up to 81% through previously unprecedented N-phthaloylguanidines. This protocol also features wide substrate scope and mild conditions.
RESUMEN
Ring A halogenated 13α-, 13ß-, and 17-deoxy-13α-estrone derivatives were synthesised with N-halosuccinimides as electrophile triggers. Substitutions occurred at positions C-2 and/or C-4. The potential inhibitory action of the halogenated estrones on human aromatase, steroid sulfatase, or 17ß-hydroxysteroid dehydrogenase 1 activity was investigated via in vitro radiosubstrate incubation. Potent submicromolar or low micromolar inhibitors were identified with occasional dual or multiple inhibitory properties. Valuable structure-activity relationships were established from the comparison of the inhibitory data obtained. Kinetic experiments performed with selected compounds revealed competitive reversible inhibition mechanisms against 17ß-hydroxysteroid dehydrogenase 1 and competitive irreversible manner in the inhibition of the steroid sulfatase enzyme.
Asunto(s)
Aromatasa/metabolismo , Inhibidores Enzimáticos/farmacología , Estradiol Deshidrogenasas/antagonistas & inhibidores , Estrógenos/biosíntesis , Estrona/farmacología , Esteril-Sulfatasa/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estradiol Deshidrogenasas/metabolismo , Estrona/síntesis química , Estrona/química , Halogenación , Humanos , Conformación Molecular , Esteril-Sulfatasa/metabolismo , Relación Estructura-ActividadRESUMEN
The synthesis and in vitro cytotoxic characteristics of new imidazo[1,2-b]pyrazole-7-carboxamides were investigated. Following a hit-to-lead optimization exploiting 2D and 3D cultures of MCF-7 human breast, 4T1 mammary gland, and HL-60 human promyelocytic leukemia cancer cell lines, a 67-membered library was constructed and the structure-activity relationship (SAR) was determined. Seven synthesized analogues exhibited sub-micromolar activities, from which compound 63 exerted the most significant potency with a remarkable HL-60 sensitivity (IC50 = 0.183 µM).
Asunto(s)
Antineoplásicos/farmacología , Imidazoles/farmacología , Leucemia Promielocítica Aguda/tratamiento farmacológico , Pirazoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Células HL-60 , Humanos , Imidazoles/síntesis química , Imidazoles/química , Leucemia Promielocítica Aguda/patología , Células MCF-7 , Ratones , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-ActividadRESUMEN
A facile Pd-catalyzed C(sp2)-N coupling to provide a range of 2- or 4-[(subst.)phenyl]amino-13α-estrone derivatives has been achieved under microwave irradiation. The reactions were mediated with the use of Pd(OAc)2 as a catalyst and KOt-Bu as a base in the presence of X-Phos as a ligand. The desired products have been obtained in good to excellent yields. The nature and the position of the aniline substituent at the aromatic ring influenced the outcome of the couplings. 2-Amino-13α-estrone was also synthesized in a two-step protocol including an amination of 2-bromo-13α-estrone 3-benzyl ether with benzophenone imine and subsequent hydrogenolysis.
RESUMEN
The syntheses of monosaccharide-d-secoestrone conjugates are reported. They were prepared from 3-(prop-2-inyloxy)-d-secoestrone alcohol or oxime and monosaccharide azides via Cu(I)-catalyzed azide-alkyne cycloaddition reactions (CuAAC). The antiproliferative activities of the conjugates were investigated in vitro against a panel of human adherent cancer cell lines (HeLa, A2780 and MCF-7) by means of MTT assays. The protected d-glucose-containing d-secoestrone oxime bioconjugate (24b) proved to be the most effective with an IC50 value in the low micromolar range against A2780 cell line.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Estrona/análogos & derivados , Glucosa/química , Glucosa/farmacología , Glicoconjugados/química , Glicoconjugados/farmacología , Alquinos/química , Antineoplásicos/síntesis química , Azidas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Reacción de Cicloadición , Estrona/síntesis química , Estrona/química , Estrona/farmacología , Glucosa/síntesis química , Glicoconjugados/síntesis química , Células HeLa , Humanos , Células MCF-7 , Monosacáridos/síntesis química , Monosacáridos/química , Monosacáridos/farmacología , Neoplasias/tratamiento farmacológico , Oximas/síntesis química , Oximas/química , Oximas/farmacologíaRESUMEN
Various novel arylated estrone derivatives, such as 2-aryl-, 4-aryl- and 2,4-diaryl-estrones, by Suzuki-Miyaura reactions. While the synthesis of 4-arylestrones could be carried out under standard conditions, the synthesis of 2-arylestrones and 2,4-diarylestrones required a thorough optimization of the conditions and it proved to be important to use sterically encumbered biaryl ligands. The best results were obtained by the use of RuPhos. Combination of developed Suzuki coupling reactions with subsequent cyclization reactions afforded more complex hybrid structures, containing dibenzofuran, benzocoumarin and steroid moieties. These derivatives were tested as pancreatic lipase inhibitors and it was found that most of the compounds exhibited inhibition of pancreatic lipase but the maximum inhibitory potential was shown by 4-arylestrones. All of the synthesized derivatives showed inhibitory values in the range of 0.82±0.01-59.7±3.12µM. The biological activity was also rationalized on the bases of docking studies.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Estrona/farmacología , Lipasa/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estrona/síntesis química , Estrona/química , Humanos , Lipasa/metabolismo , Estructura Molecular , Páncreas/enzimología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Novel 13α-estrone derivatives were synthesized by Sonogashira coupling. Transformations of 2- or 4-iodo regioisomers of 13α-estrone and its 3-methyl ether were carried out under different conditions in a microwave reactor. The 2-iodo isomers were reacted with para-substituted phenylacetylenes using Pd(PPh3)4 as catalyst and CuI as a cocatalyst. Coupling reactions of 4-iodo derivatives could be achieved by changing the catalyst to Pd(PPh3)2Cl2. The product phenethynyl derivatives were partially or fully saturated. Compounds bearing a phenolic OH group furnished benzofurans under the conditions used for the partial saturation. The inhibitory effects of the compounds on human placental 17ß-hydroxysteroid dehydrogenase type 1 isozyme (17ß-HSD1) were investigated by an in vitro radiosubstrate incubation method. Certain 3-hydroxy-2-phenethynyl or -phenethyl derivatives proved to be potent 17ß-HSD1 inhibitors, displaying submicromolar IC50 values.
RESUMEN
An efficient synthesis of several N-[(1-benzyl-1,2,3-triazol-4-yl)methyl]carboxamides in the 13ß- and 13α-d-secoestrone series is reported. Novel triazoles were synthesized via the Cu(I)-catalyzed azide-alkyne cycloaddition of steroidal alkynyl carboxamides and p-substituted benzyl azides. Each of the products was evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF-7, A431 and A2780). Some of them exhibited activities similar to those of the reference agent cisplatin. On change of the substitution pattern of the benzyl group of the azide, great differences in the cell growth-inhibitory properties were observed. The p-alkylbenzyl-substituted triazoles selectively exerted high cytostatic action against A2780 cells, with IC50 values of 1 µM. We investigated the potential inhibitory action exerted on the human 17ß-HSD1 activity of the new secosteroids. Three triazoles effectively suppressed the estrone to 17ß-estradiol conversion with IC50 values in low micromolar range.
Asunto(s)
Antineoplásicos/farmacología , Compuestos de Bencilo/farmacología , Inhibidores Enzimáticos/farmacología , Estradiol Deshidrogenasas/antagonistas & inhibidores , Estrona/análogos & derivados , Triazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos de Bencilo/síntesis química , Compuestos de Bencilo/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estradiol Deshidrogenasas/metabolismo , Estrona/síntesis química , Estrona/química , Estrona/farmacología , Células HeLa , Humanos , Células MCF-7 , Estructura Molecular , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
The inhibitory effects of 13-epimeric estrones, D-secooxime and D-secoalcohol estrone compounds on human placental 17ß-hydroxysteroid dehydrogenase type 1 isozyme (17ß-HSD1) were investigated. The transformation of estrone to 17ß-estradiol was studied by an in vitro radiosubstrate incubation method. 13α-Estrone inhibited the enzyme activity effectively with an IC50 value of 1.2 µM, which indicates that enzyme affinity is similar to that of the natural estrone substrate. The 13ß derivatives and the compounds bearing a 3-hydroxy group generally exerted stronger inhibition than the 13α and 3-ether counterparts. The 3-hydroxy-13ß-D-secoalcohol and the 3-hydroxy-13α-D-secooxime displayed an outstanding cofactor dependence, i.e. more efficient inhibition in the presence of NADH than NADPH. The 3-hydroxy-13ß-D-secooxime has an IC50 value of 0.070 µM and is one of the most effective 17ß-HSD1 inhibitors reported to date in the literature.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Estradiol Deshidrogenasas/antagonistas & inhibidores , Estrona/análogos & derivados , Estrona/farmacología , Citosol/efectos de los fármacos , Citosol/enzimología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Estradiol Deshidrogenasas/metabolismo , Estrona/química , Humanos , Conformación Molecular , Relación Estructura-ActividadRESUMEN
The syntheses of C-13 epimeric 3-[(1-benzyl-1,2,3-triazol-4-yl)methoxy]-d-secoestrones are reported. Triazoles were prepared from 3-(prop-2-inyloxy)-d-secoalcohols and p-substituted benzyl azides via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The antiproliferative activities of the products and their precursors were determined in vitro against a panel of human adherent cervical (HeLa, SiHa and C33A), breast (MCF-7, MDA-MB-231, MDA-MB-361 and T47D) and ovarian (A2780) cell lines by means of MTT assays. The orientation of the angular methyl group and the substitution pattern of the benzyl group of the azide greatly influenced the cell growth-inhibitory potential of the compounds. The 13ß derivatives generally proved to be more potent than their 13α counterparts. Introduction of a benzyltriazolylmethyl group onto the 3-OH position seemed to be advantageous. One 13α compound containing an unsubstituted benzyltriazolyl function displayed outstanding antiproliferative activities against three cell lines.
Asunto(s)
Alcoholes/química , Alcoholes/síntesis química , Proliferación Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Alcoholes/farmacología , Alquinos/química , Azidas/química , Catálisis , Ciclo Celular/efectos de los fármacos , Reacción de Cicloadición , Humanos , Células MCF-7 , Triazoles/químicaRESUMEN
2'-Deoxynucleoside conjugates of 13α-estrone were synthesized by applying the copper-catalyzed alkyne-azide click reaction (CuAAC). For the introduction of the azido group the 5'-position of the nucleosides and a propargyl ether functional group on the 3-hydroxy group of 13α-estrone were chosen. The best yields were realized in our hands when the 3'-hydroxy groups of the nucleosides were protected by acetyl groups and the 5'-hydroxy groups were modified by the tosyl-azide exchange method. The commonly used conditions for click reaction between the protected-5'-azidonucleosides and the steroid alkyne was slightly modified by using 1.5 equivalent of Cu(I) catalyst. All the prepared conjugates were evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cell lines (HeLa, MCF-7 and A2780) and the potential inhibitory activity of the new conjugates on human 17ß-hydroxysteroid dehydrogenase 1 (17ß-HSD1) was investigated via in vitro radiosubstrate incubation. Some protected conjugates displayed moderate antiproliferative properties against a panel of human adherent cancer cell lines (the protected cytidine conjugate proved to be the most potent with IC50 value of 9 µM). The thymidine conjugate displayed considerable 17ß-HSD1 inhibitory activity (IC50 = 19 µM).
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Antineoplásicos , Inhibidores Enzimáticos , Proteínas de Neoplasias/antagonistas & inhibidores , Nucleósidos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Química Clic , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Células HeLa , Humanos , Células MCF-7 , Nucleósidos/síntesis química , Nucleósidos/química , Nucleósidos/farmacologíaRESUMEN
2-Methoxyestradiol (ME), one of the most widely investigated A-ring-modified metabolites of estrone, exerts significant anticancer activity on numerous cancer cell lines. Its pharmacological actions, including cell cycle arrest, microtubule disruption and pro-apoptotic activity, have already been described in detail. The currently tested D-ring-modified analogue of estrone, D-homoestrone, selectively inhibits cervical cancer cell proliferation and induces a G2/M phase cell cycle blockade, resulting in the development of apoptosis. The question arose of whether the difference in the chemical structures of these analogues can influence the mechanism of anticancer action. The aim of the present study was therefore to elucidate the molecular contributors of intracellular processes induced by D-homoestrone in HeLa cells. Apoptosis triggered by D-homoestrone develops through activation of the intrinsic pathway, as demonstrated by determination of the activities of caspase-8 and -9. It was revealed that D-homoestrone-treated HeLa cells are not able to enter mitosis because the cyclin-dependent kinase 1-cyclin B complex loses its activity, resulting in the decreased inactivation of stathmin and a concomitant disturbance of microtubule formation. However, unlike 2-ME, D-homoestrone does not exert a direct effect on tubulin polymerization. These results led to the conclusion that the D-homoestrone-triggered intracellular processes resulting in a cell cycle arrest and apoptosis in HeLa cells differ from those in the case of 2-ME. This may be regarded as an alternative mechanism of action among steroidal anticancer compounds.
Asunto(s)
Estrona/análogos & derivados , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Mitosis/efectos de los fármacos , Neoplasias del Cuello Uterino/patología , Apoptosis/efectos de los fármacos , Proteína Quinasa CDC2 , Caspasa 8/metabolismo , Caspasa 9/metabolismo , Proliferación Celular/efectos de los fármacos , Ciclina B/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Estrona/química , Estrona/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Cinética , Fosforilación/efectos de los fármacos , Polimerizacion/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Tubulina (Proteína)/metabolismo , Neoplasias del Cuello Uterino/enzimologíaRESUMEN
Novel androstenoarylpyrazolines were synthesized stereoselectively by the BF3-induced intramolecular 1,3-dipolar cycloaddition of alkenyl hydrazones obtained from a steroidal D-seco-aldehyde with differently substituted arylhydrazines. The reaction rates were observed to be affected significantly by the electronic character of the substituents on the aromatic moiety. The cyclizations are assumed to follow a stepwise rather than a pure concerted mechanism, to afford arylpyrazolidines as primary products. Spontaneous oxidation of the saturated N,N-heterocycles under the reaction conditions led to pyrazoline derivatives in good to excellent yields. In in vitro antiproliferative studies on a panel of breast cancer cells (MCF7, T47D, MDA-MB-231, and MDA-MB-361), some of the 3-deacetylated cycloadducts exerted marked growth inhibitory activities, with IC(50) values in the range 3.56-9.32 µm, which are comparable to that for the reference agent cisplatin.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Ácidos de Lewis/química , Pirazoles/química , Pirazoles/farmacología , Esteroides/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pirazoles/síntesis químicaRESUMEN
Novel types of 17-exo-heterocycles in the Δ(5) androstene series carrying an 1,3,4-oxadiazole moiety were efficiently synthesized via aldehyde N-acylhydrazone intermediates, obtained from the microwave-assisted condensation of 3ß-hydroxy- or 3ß-acetoxyandrost-5-ene-17ß-carbaldehyde with different acylhydrazides. The subsequent phenyl iodonium diacetate-induced oxidative cyclization proceeded under mild conditions. The synthesized compounds were subjected to in vitro pharmacological studies to investigate their antiproliferative activities on four malignant adherent cell lines (HeLa, MCF7, A2780 and A431), and exhibited the highest potency against HeLa cells, some of them revealing action comparable to that of the reference agent cisplatin.
Asunto(s)
Antineoplásicos/química , Oxadiazoles/química , Esteroles/química , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células HeLa , Humanos , Microondas , Oxadiazoles/síntesis química , Oxadiazoles/toxicidad , Oxidación-ReducciónRESUMEN
Efficient synthesis of novel 16-spiroisoxazolines in the androst-5-ene series was carried out by 1,3-dipolar cycloadditions of different aryl nitrile oxides to 3ß-acetoxy-16-methylene-androst-5-en-17-one. During the intermolecular ring closures, the attack of the O terminus of the nitrile oxide dipole from the α side on C-16 predominated for steric reasons permitting the reactions to occur in a regio- and stereoselective manner. The minor isomers in which the angular methyl group on C-13 and the O atom of the isoxazoline heteroring were in the ß, ß-cis orientation were obtained in a yield of only ~10 %. Moreover, the conversions were influenced to a certain extent by the substituents on the aromatic moiety of the 1,3-dipoles. The stereostructures of the related diastereomers were confirmed by 2D NMR methods. Deacetylation of the primarily formed main products resulted in the corresponding 3ß-OH analogs, which were further reduced to furnish 3ß, 17ß-diols. All of the synthetized compounds were subjected to in vitro pharmacological studies in order to investigate their antiproliferative effects on three malignant human adherent cell lines (HeLa, MCF7, and A431).