RESUMEN
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which plays a center role in the phosphorylation of a wide variety of proteins, generally leading to their inactivation. As such, GSK-3 is viewed as a therapeutic target. An ever-increasing number of small organic molecule inhibitors of GSK-3 have been reported. Phenylmethylene hydantoins are known to exhibit a wide range of inhibitory activities including for GSK-3ß. A family of fourteen 2-heterocycle substituted methylene hydantoins (14, 17-29) were prepared and evaluated for the inhibition of GSK-3ß at 25 µM. The IC50 values of five of these compounds was determined; the two best inhibitors are 5-[(4'-chloro-2-pyridinyl)methylene]hydantoin (IC50 = 2.14 ± 0.18 µM) and 5-[(6'-bromo-2-pyridinyl)methylene]hydantoin (IC50 = 3.39 ± 0.16 µM). The computational docking of the compounds with GSK-3ß (pdb 1q41) revealed poses with hydrogen bonding to the backbone at Val135. The 5-[(heteroaryl)methylene]hydantoins did not strongly inhibit other metalloenzymes, demonstrating poor inhibitory activity against matrix metalloproteinase-12 at 25 µM and against human carbonic anhydrase at 200 µM, and were not inhibitors for Staphylococcus aureus pyruvate carboxylase at concentrations >1000 µM.
RESUMEN
Two (4-hydroxyphenyl) substituted polycyclic carbocycles were prepared and assayed for estrogen receptor activity. 4-(4-Hydroxyphenyl)tricyclo[3.3.1.13,7]decane-1-methanol (5a/b) and 7-(4-hydroxyphenyl)spiro[3.5]nonan-2-ol ((±)-11) were found to be potent ERß agonists (1.9 ± 0.4 nM and 6.2 ± 1.4 nM respectively) in a cell-based functional assay. Furthermore, both 5a/b and 11 were highly selective for ERß over ERα (377 and 1,100-fold selective respectively). While neither compound inhibited CYP2D6 or CYP3A4 at concentrations up to 62.5 µM, 5a/b did have weak binding to CYP2C9 with an IC50 of 10 ± 0.5 µM. Computational assessment of 5a/b and 11 predicted the most probable site of metabolism would be ortho to the phenolic hydroxyl group.
Asunto(s)
Receptor beta de Estrógeno , Estrógenos , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Fenoles/químicaRESUMEN
Development of estrogen therapies targeting the ß (ERß) but not α (ERα) estrogen receptor is critically needed for the treatment of negative menopausal symptoms, as ERα activation increases health risks like cancer. Here, we determined the effects of long-term oral treatment with EGX358, a novel highly selective ERß agonist, on memory, vasodilation, and affect in young ovariectomized mice. Mice were orally gavaged daily for 9 weeks with vehicle, 17ß-estradiol (E2), the ERß agonist diarylpropionitrile (DPN), or EGX358 at doses that enhance memory when delivered acutely. Tail skin temperature was recorded as a proxy for vasodilation following injection of vehicle or senktide, a tachykinin receptor 3 agonist used to model hot flashes. Anxiety-like behavior was assessed in the open field (OF) and elevated plus maze (EPM), and depression-like behavior was measured in the tail suspension (TST) and forced swim tests (FST). Finally, memory was assessed in object recognition (OR) and object placement (OP) tasks. E2, DPN, and EGX358 reduced senktide-mediated increases in tail skin temperature compared to vehicle. All three treatments also enhanced memory in the OR and OP tasks, whereas vehicle did not. Although E2 increased time spent in the center of the OF, no other treatment effects were observed in the OF, EPM, TST, or FST. These data suggest that long-term ERß activation can reduce hot flash-like symptoms and enhance spatial and object recognition memories in ovariectomized mice. Thus, the highly selective ERß agonist EGX358 may be a promising avenue for reducing menopause-related hot flashes and memory dysfunction.
Asunto(s)
Receptor beta de Estrógeno , Preparaciones Farmacéuticas , Administración Oral , Animales , Estradiol/farmacología , Receptor alfa de Estrógeno , Femenino , Humanos , Ratones , Nitrilos/farmacología , Ovariectomía , VasodilataciónRESUMEN
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
The spliceostatins/thailanstatins are a family of linear peptides/polyketides that inhibit pre-mRNA splicing, and as such act as potent cytotoxic compounds. These compounds generally contain 9 stereocenters spread over a common (2Z,4S)-4-acetoxy-2-butenamide fragment, an (all-cis)-2,3,5,6-tetrasubstituted tetrahydropyran fragment and a terminal oxane ring joined by a dienyl chain. Due to the impressive antitumor properties of these compounds, along with their complex structure, a number of total syntheses have been reported. This review will compare the synthetic strategies reported through the end of 2019.
RESUMEN
Through a structure-based drug design project (SBDD), potent small molecule inhibitors of pyruvate carboxylase (PC) have been discovered. A series of α-keto acids (7) and α-hydroxycinnamic acids (8) were prepared and evaluated for inhibition of PC in two assays. The two most potent inhibitors were 3,3'-(1,4-phenylene)bis[2-hydroxy-2-propenoic acid] (8u) and 2-hydroxy-3-(quinoline-2-yl)propenoic acid (8v) with IC50 values of 3.0⯱â¯1.0⯵M and 4.3⯱â¯1.5⯵M respectively. Compound 8v is a competitive inhibitor with respect to pyruvate (Kiâ¯=â¯0.74⯵M) and a mixed-type inhibitor with respect to ATP, indicating that it targets the unique carboxyltransferase (CT) domain of PC. Furthermore, compound 8v does not significantly inhibit human carbonic anhydrase II, matrix metalloproteinase-2, malate dehydrogenase or lactate dehydrogenase.
Asunto(s)
Ácidos Cumáricos/uso terapéutico , Piruvato Carboxilasa/antagonistas & inhibidores , Ácidos Cumáricos/farmacología , Diseño de Fármacos , HumanosRESUMEN
A short and efficient route to 4-(4-hydroxyphenyl)cycloheptanemethanol was developed, which resulted in the preparation of a mixture of 4 stereoisomers. The stereoisomers were separated by preparative HPLC, and two of the stereoisomers identified by X-ray crystallography. The stereoisomers, as well as a small family of 4-cycloheptylphenol derivatives, were evaluated as estrogen receptor-beta agonists. The lead compound, 4-(4-hydroxyphenyl)cycloheptanemethanol was selective for activating ER relative to seven other nuclear hormone receptors, with 300-fold selectivity for the ß over α isoform and with EC50 of 30-50â¯nM in cell-based and direct binding assays.
Asunto(s)
Antineoplásicos/farmacología , Cicloheptanos/farmacología , Receptor beta de Estrógeno/agonistas , Estrógenos/farmacología , Metanol/farmacocinética , Fenoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Cicloheptanos/síntesis química , Cicloheptanos/química , Cicloheptanos/farmacocinética , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Estrógenos/síntesis química , Estrógenos/química , Humanos , Células MCF-7 , Metanol/síntesis química , Metanol/química , Modelos Moleculares , Estructura Molecular , Fenoles/síntesis química , Fenoles/química , Relación Estructura-ActividadRESUMEN
Estrogen receptor-beta (ERß) is a drug target for memory consolidation in postmenopausal women. Herein is reported a series of potent and selective ERß agonists (SERBAs) with in vivo efficacy that are A-C estrogens, lacking the B and D estrogen rings. The most potent and selective A-C estrogen is selective for activating ER relative to seven other nuclear hormone receptors, with a surprising 750-fold selectivity for the ß over α isoform and with EC50s of 20-30 nM in cell-based and direct binding assays. Comparison of potency in different assays suggests that the ER isoform selectivity is related to the compound's ability to drive the productive conformational change needed to activate transcription. The compound also shows in vivo efficacy after microinfusion into the dorsal hippocampus and after intraperitoneal injection (0.5 mg/kg) or oral gavage (0.5 mg/kg). This simple yet novel A-C estrogen is selective, brain penetrant, and facilitates memory consolidation.
Asunto(s)
Receptor beta de Estrógeno/agonistas , Estrógenos/química , Estrógenos/farmacología , Consolidación de la Memoria/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Relación Dosis-Respuesta a Droga , Receptor beta de Estrógeno/química , Receptor beta de Estrógeno/metabolismo , Estrógenos/metabolismo , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Conformación Proteica , Relación Estructura-ActividadRESUMEN
The reaction of tricarbonyl and (dicarbonyl)triphenylphosphine (1-methoxycarbonyl-pentadientyl)iron(1+) cations 7 and 8 with methyl lithium, NaBH3CN, or potassium phthalimide affords (pentenediyl)iron complexes 9a-c and 11a-b, while reaction with dimethylcuprate, gave (E,Z-diene)iron complexes 10 and 12. Oxidatively induced-reductive elimination of 9a-c gave vinylcyclopropanecarboxylates 17a-c. The optically active vinylcyclopropane (+)-17a, prepared from (1S)-7, undergoes olefin cross-metathesis with excess (+)-18 to yield (+)-19, a C9-C16 synthon for the antifungal agent ambruticin. Alternatively reaction of 7 with methanesulfonamide or trimethylsilylazide gave (E,E-diene)iron complexes 14d and e. Huisgen [3+2] cyclization of the (azidodienyl)iron complex 14e with alkynes afforded triazoles 25a-e.
RESUMEN
The title compound, C6H9NO4·H2O [systematic name: (αR,1R,2S)-rel-α-amino-2-carb-oxy-cyclo-propane-acetic acid monohydrate], crystallizes with two organic mol-ecules and two water mol-ecules in the asymmetric unit. The space group is P21 and the organic mol-ecules are enanti-omers, thus this is an example of a 'false conglomerate' with two mol-ecules of opposite handedness in the asymmetric unit (r.m.s. overlay fit = 0.056â Å for one mol-ecule and its inverted partner). Each mol-ecule exists as a zwitterion, with proton transfer from the amino acid carb-oxy-lic acid group to the amine group. In the crystal, the components are linked by N-Hâ¯O and O-Hâ¯O hydrogen bonds, generating (100) sheets. Conformationally restricted glutamate analogs are of inter-est due to their selective activation of different glutamate receptors, and the naturally occurring (+)-CCG-III is an inhibitor of glutamate uptake and the key geometrical parameters are discussed.
RESUMEN
A series of eight stereoisomeric N-(tetrahydroxy bicyclo-[5.1.0]oct-2S*-yl)phthalimides were prepared in one to four steps from N-(bicyclo[5.1.0]octa-3,5-dien-2-yl)phthalimide (±)-7, which is readily available from cyclooctatetraene (62 % yield). The structural assignments of the stereoisomers were established by (1) Hâ NMR spectral data as well as X-ray crystal structures for certain members. The outcomes of several epoxydiol hydrolyses, particularly ring contraction and enlargement, are of note. The isomeric phthalimides as well as the free amines did not exhibit ß-glucosidase inhibitory activity at a concentration of less than 100â µM.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Ftalimidas/síntesis química , Alcoholes del Azúcar/síntesis química , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacología , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Ftalimidas/química , Ftalimidas/farmacología , Estereoisomerismo , Alcoholes del Azúcar/química , Alcoholes del Azúcar/farmacología , beta-Galactosidasa/antagonistas & inhibidoresRESUMEN
Various estrogen analogs were synthesized and tested for binding to human ERα using a fluorescence polarization displacement assay. Binding affinity and orientation were also predicted using docking calculations. Docking was able to accurately predict relative binding affinity and orientation for estradiol, but only if a tightly bound water molecule bridging Arg394/Glu353 is present. Di-hydroxyl compounds sometimes bind in two orientations, which are flipped in terms of relative positioning of their hydroxyl groups. Di-hydroxyl compounds were predicted to bind with their aliphatic hydroxyl group interacting with His524 in ERα. One nonsteroid-based dihdroxyl compound was 1000-fold specific for ERß over ERα, and was also 25-fold specific for agonist ERß versus antagonist activity. Docking predictions suggest this specificity may be due to interaction of the aliphatic hydroxyl with His475 in the agonist form of ERß, versus with Thr299 in the antagonist form. But, the presence of this aliphatic hydroxyl is not required in all compounds, since mono-hydroxyl (phenolic) compounds bind ERα with high affinity, via hydroxyl hydrogen bonding interactions with the ERα Arg394/Glu353/water triad, and van der Waals interactions with the rest of the molecule.
Asunto(s)
Estradiol/química , Receptor alfa de Estrógeno/química , Radical Hidroxilo/síntesis química , Femenino , Humanos , Radical Hidroxilo/química , Relación Estructura-ActividadRESUMEN
The racemic (6-cyclo-heptadienyl)Fe(CO)(3)(+) cation ((±)-7), prepared from cyclooctatetraene, was treated with a variety of carbon and heteroatom nucleophiles. Attack took place at the less hindered C(1) dienyl carbon and decomplexation of the (cycloheptadiene)Fe(CO)(3) complexes gave products rich in functionality for further synthetic manipulation. In particular, a seven-step route was developed from racemic (6-styryl-2,4-cycloheptadien-1-yl)phthalimide ((±)-9 d) to afford the optically active aminocycloheptitols (-)-20 and (+)-20.
RESUMEN
Transformation of the simple hydrocarbon cyclooctatetraene into a variety of polycyclic skeletons was achieved by sequential coordination to iron, reaction with electrophiles followed by allylated nucleophiles, decomplexation and olefin metathesis.
RESUMEN
A short, 4-step route to the scaffold of frondosin A and B is reported. The [1-methoxycarbonyl-5-(2',5'-dimethoxyphenyl)pentadienyl]Fe(CO)(3)(+) cation was prepared in two steps from (methyl 6-oxo-2,4-hexadienoate)Fe(CO)(3). Reaction of this cation with isopropenyl Grignard or cyclohexenyllithium reagents affords (2-alkenyl-5-aryl-1-methoxycarbonyl-3-pentene-1,5-diyl)Fe(CO)(3) along with other addition products. Oxidative decomplexation of these (pentenediyl)iron complexes, utilizing CuCl(2), affords 6-aryl-3-methoxycarbonyl-1,4-cycloheptadienes via the presumed intermediacy of a cis-divinylcyclopropane.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Química Farmacéutica/métodos , Compuestos Férricos/síntesis química , Hierro/química , Alcadienos/química , Animales , Organismos Acuáticos/química , Enfermedades Autoinmunes/tratamiento farmacológico , Compuestos Bicíclicos con Puentes/farmacología , Cationes/química , Compuestos Férricos/farmacología , Humanos , Interleucina-8/antagonistas & inhibidores , Interleucina-8/inmunología , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Oxidación-Reducción , Poríferos/química , Receptores de Interleucina-8/antagonistas & inhibidores , Receptores de Interleucina-8/inmunologíaRESUMEN
The syntheses of 12 stereochemically diverse polyhydroxyl aminocyclohexane ("aminocyclitols") derivatives are described. These short syntheses require 2-5 steps from N-(2,4-cyclohexadien-1-yl)phthalimide, which is prepared in two steps from tricarbonyl(cyclohexadienyl)iron(1+). The relative stereochemistries of the aminocyclitols were assigned by (1)H NMR spectroscopy as well as X-ray diffraction analysis.
Asunto(s)
Aminas/química , Ciclohexanos/síntesis química , Cristalografía por Rayos X , Hidrogenación , Hidroxilación , Modelos Moleculares , Estructura MolecularRESUMEN
Complexation of (tricarbonyl)iron to an acyclic diene serves to protect the ligand against oxidation, reduction and cycloaddition reactions while the steric bulk of this adjunct serves to direct the approach reagents to unsaturated groups attached to the diene onto the face opposite to iron. Furthermore, the Fe(CO)(3) moiety can serve to stabilize carbocation centers adjacent to the diene (i.e. pentadienyl-iron cations). Recent applications of these reactivities to the synthesis of polyene, cyclopropane, cycloheptadiene and cyclohexenone containing natural products or analogs will be presented.
RESUMEN
The reactivity of (2-alkenyl-3-pentene-1,5-diyl)iron complexes toward olefin metathesis, cycloaddition, and mild oxidations (MnO 2 or mCPBA) was examined. Cycloaddition reactions were observed to occur with modest diastereoselectivity (33-63% de). Decomplexation of the (3-pentenediyl) ligand may be accomplished by oxidation with either CAN or alkaline hydrogen peroxide to afford vinylcyclopropanecarboxylates or divinylcyclopropanecarboxylates. Reduction of the latter, followed by Cope rearrangement generates cycloheptadienylmethanols. These studies demonstrate that (2-alkenyl-3-pentene-1,5-diyl)iron complexes can serve as organometallic scaffolds for the preparation of a wide variety of structural motifs containing up to 5 contiguous stereocenters.
Asunto(s)
Cicloheptanos/síntesis química , Ciclopropanos/síntesis química , Compuestos Férricos/química , Compuestos de Vinilo/síntesis química , Alquenos/química , Ciclización , Cicloheptanos/química , Ciclopropanos/química , Compuestos Férricos/síntesis química , Ligandos , Modelos Moleculares , Conformación Molecular , Oxidación-Reducción , Estereoisomerismo , Compuestos de Vinilo/químicaRESUMEN
The cyclopropane containing betaine, rac-dysibetaine CPa, was prepared from (1-methoxycarbonylpentadienyl)-Fe(CO)2PPh3+ by nucleophilic addition of nitromethane anion followed by oxidatively induced reductive elimination.
Asunto(s)
Betaína/análogos & derivados , Ciclopropanos/síntesis química , Compuestos Férricos/química , Compuestos Organometálicos/química , Betaína/síntesis química , Betaína/química , Cristalografía por Rayos X , Ciclopropanos/química , Espectroscopía de Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/normas , Modelos Moleculares , Conformación Molecular , Estándares de Referencia , EstereoisomerismoRESUMEN
A route to the carbon skeleton of the proposed structure for heteroscyphic acid A was developed utilizing a Mn(III)/Cu(II) mediated oxidative free-radical cyclization and nucleophilic addition to (3-methylpentadienyl)iron(1+) cation.