RESUMEN
Oligomeric procyanidins containing 4alpha-linked epicatechin units are rare in nature and have hitherto not been accessible through stereoselective synthesis. We report herein the preparation of the prototypical dimer, epicatechin-4alpha,8-epicatechin (6), by reaction of the protected 4-ketones 11a,b with aryllithium reagents derived by halogen/metal exchange from the aryl bromides 26a,b. Removal of the 4-hydroxyl group from the resulting tertiary benzylic alcohols 27a,b was effected by tri-n-butyltin hydride and trifluoroacetic acid in a completely stereoselective manner, resulting in hydride delivery exclusively from the beta face. If benzyl was chosen for protection of the 3-hydroxyls, all protective groups could subsequently be removed in a single step by hydrogenolysis. tert-Butyldimethylsilyl groups, on the other hand, permitted selective deprotection of the 3-hydroxyls in preparation for their subsequent acylation with tri-O-benzylgalloyl chloride. Only monogalloylation at the "bottom" 3-hydroxyl took place when 28c was acylated under the previously reported conditions, reflecting the increased steric hindrance of the "top" 3-hydroxyl group in 28c compared with its 4beta,8-isomer 3. The preparation of compounds 14 and 17 containing phloroglucinol trimethyl ether in the 4alpha and 4beta linkages to epicatechin is also described. The 8-position of the bromine atom in 19, previously conjectured in analogy to the structurally characterized tetramethyl ether 20, was confirmed by transformation of both compounds into the common derivative 25.
Asunto(s)
Biflavonoides , Catequina/química , Flavonoides , Isomerismo , Fenoles/química , Fenoles/farmacología , Polímeros/química , Polímeros/farmacología , Proantocianidinas , Análisis EspectralRESUMEN
The assignment of interflavan bond regio- and stereochemistry in oligomeric proanthocyanidins has in the past relied on empirical spectroscopic techniques which are influenced by the conformation of the C rings. Only recently was the 4,8-regiochemistry of procyanidin B2 (3b) firmly established by 2-dimensional NMR methods. We describe herein the proof of 4beta-stereochemistry in 3b by oxidative degradation of the derivative 3d bearing differential (O-benzyl and O-methyl) protecting groups in its "top" and "bottom" epicatechin moieties, to (R)-(-)-2,4-diphenylbutyric acid. The key elements of the degradative process are (1) removal of the C-3 alcohol functions through a modified Barton deoxygenation employing hypophosphorous acid as the reducing agent; (2) deprotection of the "top" unit by hydrogenolysis, followed by exhaustive aryl triflate formation with N,N-bis(trifluoromethanesulfonyl)aniline and DBU in DMF; (3) hydrogenolytic deoxygenation of the "top" unit over Pearlman's catalyst with concomitant scission of the O-C2 bond; (4) selective oxidation of the "bottom" unit with NaIO4/RuCl3. The hitherto unreported absolute configuration of (-)-2,4-diphenylbutyric acid was established as R by X-ray crystal structure analysis of the (R)-(+)-alpha-methylbenzylamine salt. As a corollary, the selectivity of hydrogenolytic and solvolytic reactions of epicatechin-derived tetrasulfonates has been investigated.
Asunto(s)
Biflavonoides , Catequina/química , Flavonoides , Fenoles/síntesis química , Fenilbutiratos/síntesis química , Polímeros/síntesis química , Proantocianidinas , Alquilación , Espectroscopía de Resonancia Magnética , Oxidación-Reducción , EstereoisomerismoRESUMEN
The synthesis of the 1-amino derivative of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylic acid (1-amino-APDC), a selective metabotropic glutamate ligand, is disclosed. This compound acts as a partial agonist of the group II mGluRs and shows pronounced neuroprotective properties in the NMDA model of cell toxicity.
Asunto(s)
Fármacos Neuroprotectores/farmacología , Prolina/análogos & derivados , Receptores de Glutamato Metabotrópico/agonistas , Animales , Células CHO , Muerte Celular , Cricetinae , Agonistas de Aminoácidos Excitadores/síntesis química , Agonistas de Aminoácidos Excitadores/farmacología , Ratones , N-Metilaspartato/toxicidad , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/síntesis química , Prolina/síntesis química , Prolina/farmacologíaRESUMEN
To better characterize the roles of metabotropic glutamate receptors (mGluRs) in physiological and pathophysiological processes, there is an important need to learn more about the structural features relevant to the design of novel, high-affinity ligands that are family and subtype specific. To date, many of the biological studies that have been conducted in the area of mGluR research have made use of the agonist (1S,3R)-ACPD. This compound has been shown to act as an agonist at both the group I and group II receptors while showing little selectivity among the four subtypes belonging to these two groups. Moreover, (1S,3S)-ACPD, the cis isomer, shows negligible activity at group I receptors and is a good agonist of mGluR2. Since ACPD is itself somewhat flexible, with four distinctive conformations being identified from molecular modeling studies for the trans isomer and five conformations for the cis isomer, we believed that it would be of interest to examine the activity of an ACPD analogue that has been constrained through the introduction of a single carbon atom bridge. Accordingly, we have prepared an aminobicyclo[2.1.1]hexanedicarboxylic acid (ABHxD-I) analogue of ACPD. The synthesis of this compound was accomplished by use of an intramolecular [2 + 2] photocycloaddition reaction, in which four distinct isomers were isolated. Of these four compounds, only a single isomer, ABHxD-I (6a), was found to be a potent agonist of the mGluRs. This compound, which expresses the fully extended glutamate conformation, was found to be more potent than ACPD at all six of the eight mGluR subtypes that were investigated and to be comparable to or more potent than the endogenous ligand, glutamate, for these receptors. Interestingly, despite its fixed conformation, ABHxD-I, like glutamate, shows little subtype selectivity. Through modeling studies of ABHxD-I (6a), ABHD-VI, LY354740, (1S,3R)-ACPD, (1S, 3S)-ACPD, and l-glutamate, we conclude that the aa conformation of l-glutamate is the active conformation for both group I and group II mGluRs. Moreover, the modeling-based comparisons of these ligands suggest that the selectivity exhibited by LY354740 between the group I and group II mGluRs is not a consequence of different conformations of L-glutamate being required for recognition at these mGluRs but rather is related to certain structural elements within certain regions having a very different impact on the group I and group II mGluR activity. The enhanced potency of ABHxD-I relative to trans-ACPD commends it as a useful starting point in the design of subtype selective mGluR ligands.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/farmacología , Ácidos Dicarboxílicos/síntesis química , Ácidos Dicarboxílicos/farmacología , Agonistas de Aminoácidos Excitadores/síntesis química , Agonistas de Aminoácidos Excitadores/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Animales , Compuestos Bicíclicos con Puentes/química , Células CHO , Calcio/metabolismo , Células Cultivadas , Cerebelo/citología , Cerebelo/metabolismo , Cricetinae , AMP Cíclico/biosíntesis , Cicloleucina/análogos & derivados , Cicloleucina/química , Cicloleucina/farmacología , Ácidos Dicarboxílicos/química , Agonistas de Aminoácidos Excitadores/química , Ácido Glutámico/química , Ácido Glutámico/farmacología , Fosfatos de Inositol/metabolismo , Riñón/citología , Riñón/metabolismo , Ligandos , Modelos Moleculares , Conformación Molecular , Norbornanos/química , Norbornanos/farmacología , Ratas , Receptores de Glutamato Metabotrópico/biosíntesis , EstereoisomerismoAsunto(s)
Colorantes Fluorescentes/síntesis química , Receptores de GABA-A/metabolismo , 4-Cloro-7-nitrobenzofurazano/química , 4-Cloro-7-nitrobenzofurazano/metabolismo , Animales , Benzodiazepinonas/metabolismo , Transporte Biológico , Colesterol/metabolismo , Clonazepam/metabolismo , Colorantes Fluorescentes/metabolismo , Hipolipemiantes/metabolismo , Ácidos Indolacéticos/química , Ácidos Indolacéticos/metabolismo , Isoquinolinas/metabolismo , Ligandos , Masculino , Ratones , Microscopía Fluorescente , Mitocondrias/metabolismo , Ratas , Células Tumorales CultivadasAsunto(s)
Ácido Azetidinocarboxílico/análogos & derivados , Glutamatos/síntesis química , Receptores de Glutamato/metabolismo , Ácido Azetidinocarboxílico/farmacología , Células Cultivadas , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Glutamatos/farmacología , Metilación , Conformación Molecular , N-Metilaspartato/farmacología , Fosfatidilinositoles/metabolismo , Receptores de Glutamato/efectos de los fármacosRESUMEN
A series of 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) analogs were synthesized with the aim of developing a potent ligand for the N-methyl-D-aspartate glutamate receptor subtype. The piperidine moiety of TCP was substituted at the nitrogen position with aliphatic chains of different length or with various polar groups. A correlation between the decrease in the potency of displacement of [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-im ine maleate (MK-801) binding from bovine cortex membranes and the increase of length or polarity of the aliphatic chain was observed. Isonitrile, isothiocyanate and isoselenocyanate groups were substituted at position 4 of the thiophene ring, and the relative binding affinity and alkylating potencies of the derivatized compounds were studied. Among this set of compounds, the one carrying an isothiocyanate group at position 4 of the thiophene ring of the N-ethyl analog of TCP yielded the most efficient alkylating agent, demonstrated by its ability to irreversibly block up to 80% of the [3H]MK-801 binding sites. This affinity ligand did not significantly affect other ligand binding sites of the same N-methyl-D-aspartate receptor complex or of other receptor systems, further demonstrating its functional specificity as a potent alkylating probe for the TCP/MK-801 recognition site. Studies with a radiolabeled adduct of this isothiocyanate N-ethyl derivative, however, indicate that a substantial level of nonspecific covalent incorporation into the membranes occurs at concentrations as low as 10 nM, thereby obscuring any possibility of detecting a specifically labeled protein species.
Asunto(s)
Marcadores de Afinidad/síntesis química , Fenciclidina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Marcadores de Afinidad/metabolismo , Alquilación , Animales , Sitios de Unión , Unión Competitiva , Bovinos , Maleato de Dizocilpina/metabolismo , Femenino , Cinética , Fenciclidina/análogos & derivados , Relación Estructura-Actividad , Tiocianatos/metabolismo , Tiocianatos/farmacología , Tiofenos/metabolismo , Tiofenos/farmacologíaRESUMEN
The stereoselectivities and mechanisms of the inhibition of rat cortical acetylcholinesterase by the enantiomers of huperzine A were determined. (-)-Huperzine A was the more potent enantiomer with a Ki value of 8 nM. (+)-Huperzine A inhibited the enzyme 38-fold less potently with a Ki value of 300 nM. Racemic huperzine A was about two-fold less potent than the more active isomer, (-)-huperzine A. The mechanism of inhibition of acetylcholinesterase for all three drugs was of the mixed linear competitive type.
Asunto(s)
Corteza Cerebral/enzimología , Inhibidores de la Colinesterasa/farmacología , Sesquiterpenos/farmacología , Alcaloides , Animales , Corteza Cerebral/efectos de los fármacos , Cinética , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Huperzine A, 9-amino-13-ethylidene-11-methyl-4-azatricyclo [7.3.1.0(3,8)]trideca-3(8),6,11-trien-5-one, C15H18N2O, Mr = 242.32, monoclinic, P2(1)/n, a = 8.8574 (6), b = 12.1833 (7), c = 12.4278 (7) A, beta = 99.956 (5) degrees, V = 1320.9 (1) A3, Z = 4, Dx = 1.22 g cm-3, lambda(Cu K alpha) = 1.54178 A, mu = 5.75 cm-1, F(000) = 520, T = 296 K, RF = 6.30% for 1402 reflections with Fo greater than or equal to 5 sigma(Fo) and 183 parameters. The pyridone ring is planar and the stereochemistry of the C(11)--C(12) double bond is E.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/química , Sesquiterpenos/química , Alcaloides , Fenómenos Químicos , Química Física , Cristalización , Humanos , Conformación Molecular , Estructura Molecular , Difracción de Rayos XRESUMEN
A variety of derivatives of azetidine-2,4-dicarboxylic acid were synthesized and examined for their ability to stimulate 45Ca2+ uptake in cultures of cerebellar granule cells. Of the compounds tested, the cis-azetidine-2,4-dicarboxylic acid (10f) was found to be the most potent agent in potentiating glutamate, aspartate, or N-methyl-D-aspartate (NMDA) stimulated 45Ca2+ uptake at the NMDA receptor. The mechanism of action of 10f was further investigated in [3H]MK-801 binding assays and [3H]GABA release from cultured embryonic rat forebrain neurons. All of the results from the functional studies of azetidine 10f are consistent with a selectivity of action at the NMDA receptor. Moreover, azetidine 10f appears to exhibit a dual type of action, behaving as a glutamate-like agonist at higher concentrations and as a positive modulator at concentrations below 50 microM.