RESUMEN
The aminocarbonylation of various alkenyl and (hetero)aryl iodides was carried out using tropane-based amines of biological importance, such as 8-azabicyclo[3.2.1]octan-3-one (nortropinone) and 3α-hydroxy-8-azabicyclo[3.2.1]octane (nortropine) as N-nucleophile. Using iodoalkenes, the two nucleophiles were selectively converted to the corresponding amide in the presence of Pd(OAc)2/2 PPh3 catalysts. In the presence of several iodo(hetero)arenes, the application of the bidentate Xantphos was necessary to produce the target compounds selectively. The new carboxamides of varied structure, formed in palladium-catalyzed aminocarbonylation reactions, were isolated and fully characterized. In this way, a novel synthetic method has been developed for the producing of N-acylnortropane derivatives of biological importance.
Asunto(s)
Nortropanos/química , Nortropanos/síntesis química , Paladio/química , Catálisis , Estructura MolecularRESUMEN
A new synthetic route for formation of a central cycloheptanone intermediate leading to the nortropane alkaloid calystegine B2 is described. The approach installs the desired ketone functionality directly in a ring-closing metathesis step. The target compound was prepared over 10 steps from commercially available methyl α-d-xylopyranoside.
Asunto(s)
Metilglicósidos/química , Nortropanos/síntesis química , Alcaloides Solanáceos/síntesis química , Cicloheptanos/química , Estructura Molecular , Nortropanos/química , Alcaloides Solanáceos/química , Estereoisomerismo , Xilosa/análogos & derivados , Xilosa/químicaRESUMEN
The key step in the concise syntheses of calystegine B2 and its C-2 epimer calystegine B3 was the construction of cycloheptanone 8via an intramolecular Nozaki-Hiyama-Kishi (NHK) reaction of 9, an aldehyde containing a Z-vinyl iodide. Vinyl iodide 9 was obtained by the Stork olefination of aldehyde 10, derived from carbohydrate starting materials. Calystegines B2 (3) and B3 (4) were synthesized from d-xylose and l-arabinose derivatives respectively in 11 steps in excellent overall yields (27% and 19%).
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Nortropanos/química , Nortropanos/síntesis química , Alcaloides Solanáceos/química , Alcaloides Solanáceos/síntesis química , Aldehídos/química , Técnicas de Química Sintética , Cicloheptanos/química , Inhibidores Enzimáticos/farmacología , Glicósido Hidrolasas/antagonistas & inhibidores , Nortropanos/farmacología , Alcaloides Solanáceos/farmacología , EstereoisomerismoRESUMEN
The use of [(18)F]labelled nortropane derivative 2ß-carbomethoxy-3ß-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane (FECNT) as a dopamine transporter ligand for PET imaging is dependent on efficient radiosynthesis method. Herein, the automated synthesis of [(18)F]FECNT from its chlorinated precursor in commercially available SynChrom [(18)F] R&D module has been developed. The synthesis unit was readily configured for the one-step synthesis from corresponding chlorinated precursor. The radiolabeling process involved a classical [(18)F]fluoride nucleophilic substitution performed at 110 °C for 12 min and finally HPLC and SPE purification. Crude [(18)F]FECNT was obtained with a radiolabeling yield of 59 ± 12% (n = 5). The average uncorrected amount of [(18)F]FECNT in the final formulated dose was 2.0 ± 0.5 GBq (32 ± 7% overall decay-corrected yields) obtained with radiochemical purity over 99% and specific activity of 55 GBq/µmol. The total duration of the procedure was 80-90 min. An automated radiosynthesis of [(18)F]FECNT with high radiochemical purity may provide a simple and robust method of radiopharmaceutical preparation for routine clinical applications.
Asunto(s)
Nortropanos/síntesis química , Radiofármacos/síntesis químicaRESUMEN
An epimer of the known glycosidase inhibitor noeurostegine, galacto-noeurostegine, was synthesised in 21 steps from levoglucosan and found to be a potent, competitive and highly selective galactosidase inhibitor of Aspergillus oryzae ß-galactosidase. Galacto-noeurostegine was not found to be an inhibitor of green coffee bean α-galactosidase, yeast α-glucosidase and E. coli ß-galactosidase, whereas potent but non-competitive inhibition against sweet almond ß-glucosidase was established. The 2-deoxy-galacto-noeurostegine analogue was also prepared and found to be a less potent inhibitor of the same enzymes.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Fucosa/síntesis química , Fucosa/farmacología , Glicósido Hidrolasas/antagonistas & inhibidores , Nortropanos/síntesis química , Nortropanos/farmacología , Conformación de Carbohidratos , Espectroscopía de Resonancia Magnética con Carbono-13 , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Fucosa/química , Glicósido Hidrolasas/metabolismo , Nortropanos/químicaRESUMEN
This paper identifies the required configuration and orientation of α-glucosidase inhibitors, miglitol, α-1-C-butyl-DNJ, and α-1-C-butyl-LAB for binding to ntSI (isomaltase). Molecular dynamics (MD) calculations suggested that the flexibility around the keyhole of ntSI is lower than that of ctSI (sucrase). Furthermore, a molecular-docking study revealed that a specific binding orientation with a CH-π interaction (Trp370 and Phe648) is a requirement for achieving a strong affinity with ntSI. On the basis of these results, a new class of nortropane-type iminosugars, labystegines, hybrid iminosugars of LAB and calystegine, have been designed and synthesized efficiently from sugar-derived cyclic nitrones with intramolecular 1,3-dipolar cycloaddition or samarium iodide catalyzed reductive coupling reaction as the key step. Biological evaluation showed that our newly designed 3(S)-hydroxy labystegine (6a) inherited the selectivity against intestinal α-glucosidases from LAB, and its inhibition potency was 10 times better than that of miglitol. Labystegine, therefore, represents a promising new class of nortropane-type iminosugar for improving postprandial hyperglycemia.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Iminoazúcares/farmacología , Nortropanos/farmacología , Sacarasa/antagonistas & inhibidores , alfa-Glucosidasas/metabolismo , Arabinosa/química , Sitios de Unión/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Iminofuranosas/química , Iminoazúcares/síntesis química , Iminoazúcares/química , Intestinos/enzimología , Conformación Molecular , Simulación de Dinámica Molecular , Nortropanos/síntesis química , Nortropanos/química , Sacarasa/metabolismo , Alcoholes del Azúcar/química , Tropanos/químicaRESUMEN
The fluorine-18 labeled nortropane derivative 2ß-carbomethoxy-3ß-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane (FECNT) is a dopamine transporter (DAT) ligand. Currently, it is considered as reference for positron emission tomography imaging. Herein, the synthesis of novel precursors (N-tosyloxy-, chloro-, and bromo- analogues) for one-step radiosynthesis of [(18)F]FECNT is reported. Using the N-mesyloxy- precursor in a one-step radiosynthesis, the crude [(18)F]FECNT was obtained with the radiolabeling yield of 45 ± 10%, confirming the practical efficiency of this approach in the design of novel precursors for labeling.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Nortropanos/síntesis química , Nortropanos/metabolismo , Tomografía de Emisión de Positrones , Técnicas de Química Sintética , Ligandos , Nortropanos/química , RadioquímicaRESUMEN
Cocaine addiction is a major problem for which there is no approved pharmacotherapy. We have developed a vaccine to cocaine (dAd5GNE), based on the cocaine analog GNE linked to the capsid proteins of a serotype 5 adenovirus, designed to evoke anti-cocaine antibodies that sequester cocaine in the blood, preventing access to the CNS. To assess the efficacy of dAd5GNE in a large animal model, positron emission tomography (PET) and the radiotracer [(11)C]PE2I were used to measure cocaine occupancy of the dopamine transporter (DAT) in nonhuman primates. Repeat administration of dAd5GNE induced high anti-cocaine titers. Before vaccination, cocaine displaced PE2I from DAT in the caudate and putamen, resulting in 62±4% cocaine occupancy. In contrast, dAd5GNE-vaccinated animals showed reduced cocaine occupancy such that when anti-cocaine titers were >4 × 10(5), the cocaine occupancy was reduced to levels of <20%, significantly below the 47% threshold required to evoke the subjective 'high' reported in humans.
Asunto(s)
Anticuerpos/inmunología , Cocaína/antagonistas & inhibidores , Cocaína/inmunología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Vacunas/farmacología , Adenoviridae/química , Animales , Anticuerpos/sangre , Cápside/metabolismo , Radioisótopos de Carbono , Núcleo Caudado/diagnóstico por imagen , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/metabolismo , Cocaína/análogos & derivados , Cocaína/química , Cocaína/farmacología , Femenino , Macaca mulatta , Neuroimagen , Nortropanos/síntesis química , Putamen/diagnóstico por imagen , Putamen/efectos de los fármacos , Putamen/metabolismo , Ensayo de Unión Radioligante , Cintigrafía , Vacunas/químicaRESUMEN
A simple synthesis of the dopamine transporter ligand [(18)F]FECNT with high radiochemical yield and short synthesis time, suitable for routine production is reported. Reaction of 2ß-carbomethoxy-3ß-(4-chlorophenyl)nortropane with [(18)F]2-fluoroethyl triflate ([(18)F]FEtOTf) at room temperature for 4 min provided [(18)F]FECNT in 84% decay corrected radiochemical yield. Since [(18)F]FEtOTf was prepared from [(18)F]2-fluoroethyl bromide that was isolated from its starting material, formation of unwanted side products and the amount of expensive precursor used could be greatly reduced. The overall radiochemical yields of [(18)F]FECNT were 40% (n=29) and the total synthesis time was ca. 100 min. The average specific activity of [(18)F]FECNT was 377.4 GBq/µmol (10.2 Ci/µmol).
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/análisis , Radioisótopos de Flúor/química , Nortropanos/síntesis química , Cromatografía Líquida de Alta PresiónRESUMEN
Optically active ent-calystegine B4 was prepared in 13 steps from commercially available chiral L-dimethyl tartrate. The synthesis was achieved by the Michael addition and the aldol reaction of nitromethane to form cycloheptanone in a stereoselective manner. Reduction of the nitro group in the presence of Boc(2)O accomplished an efficient conversion to amino cycloheptanone, which readily afforded the desired ent-calystegine B4.
Asunto(s)
Nortropanos/síntesis química , Alcaloides Solanáceos/síntesis química , Estructura Molecular , Compuestos de Nitrógeno/química , EstereoisomerismoRESUMEN
A difluorinated analogue of a ring-expanded calystegine B(2) and some N-protected species were prepared via microwave-mediated transannular ring-opening of an epoxyketone. The diastereofacial selectivity of the epoxidation reaction, which delivers the key intermediate, and the regioselectivity of the transannular reactions were analyzed by density functional theory (DFT) methods. The epoxidation stereoselectivity arises from simple steric control, whereas the ring-closure reactions are subject to thermodynamic control.
Asunto(s)
Compuestos de Flúor/síntesis química , Nortropanos/síntesis química , Alcaloides Solanáceos/síntesis química , Compuestos de Flúor/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Nortropanos/química , Alcaloides Solanáceos/química , Estereoisomerismo , TermodinámicaRESUMEN
Calystegine A(3) is a naturally occurring nortropane iminosugar of which there previously have been three total syntheses. Inspired by our previous work we here report on a fourth approach using 17 steps from 2-deoxy-d-glucose applying a diastereoselective allylation protocol.
Asunto(s)
Desoxiglucosa/química , Nortropanos/síntesis química , Alcaloides Solanáceos/síntesis química , Alquilación , Conformación Molecular , Nortropanos/química , Alcaloides Solanáceos/química , EstereoisomerismoRESUMEN
(-)-Erycibelline, the dihydroxynortropane alkaloid isolated from Erycibe elliptilimba Merr. et Chun., was synthesized using a cyclic nitrone as advanced intermediate, wherein the key step was the SmI(2)-induced intramolecular reductive coupling of cyclic nitrone with aldehyde which resulted in good yield and stereoselectivity.
Asunto(s)
Alcaloides/síntesis química , Química Farmacéutica/métodos , Glicósido Hidrolasas/antagonistas & inhibidores , Nortropanos/síntesis química , Alcaloides/análisis , Alcaloides/farmacología , Animales , Convolvulaceae/química , Ciclización , Glicósido Hidrolasas/metabolismo , Humanos , Concentración 50 Inhibidora , Óxidos de Nitrógeno/química , Nortropanos/análisis , Nortropanos/farmacología , Plantas Medicinales/química , EstereoisomerismoRESUMEN
Inhibition of ß-glucuronidases has recently been shown to be useful in alleviating drug toxicity for common colon cancer chemotherapeutic CPT-11 (also called Irinotecan). We have prepared a new compound of the nortropane-type, uronic-Noeurostegine, and demonstrated that this is a competitive and potent E. coli ß-glucuronidase inhibitor, while inhibition of the mammalian ß-glucuronidase from bovine liver was found to be less significant. Although not intended, two other compounds having N-ethyl and N-(4-hydroxybutyl) substituents were also prepared in this study due to the sluggish debenzylation in the final step. The N-substituents are believed to come from reaction with the solvents used being ethanol and THF, respectively. These compounds also inhibited the two ß-glucuronidases albeit to a lesser extent compared to the parent compound. Noeurostegine and the three uronic-noeurostegines were additionally evaluated as inhibitors against a wide panel of glycosidases with the former showing potent inhibition of rat intestinal lactase and trehalase, whereas the latter was found to be inactive.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Proteínas de Escherichia coli/antagonistas & inhibidores , Glucuronidasa/antagonistas & inhibidores , Nortropanos/síntesis química , Animales , Unión Competitiva , Bovinos , Inhibidores Enzimáticos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Proteínas de Escherichia coli/metabolismo , Glucuronidasa/metabolismo , Concentración 50 Inhibidora , Intestinos/efectos de los fármacos , Intestinos/enzimología , Lactasa/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Modelos Moleculares , Nortropanos/farmacología , Unión Proteica , Ratas , Especificidad de la Especie , Trehalasa/antagonistas & inhibidores , Trehalasa/metabolismo , Ácidos Urónicos/químicaRESUMEN
The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are described. Extensive structure-activity relationship (SAR) studies of the lead compound 20f led to the identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays. Compound 36j demonstrated an attractive in vitro and in vivo profile for further development.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Descubrimiento de Drogas , Hiperglucemia/tratamiento farmacológico , Nortropanos/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Modelos Animales de Enfermedad , Prueba de Tolerancia a la Glucosa , Concentración 50 Inhibidora , Ratones , Nortropanos/química , Nortropanos/uso terapéutico , RatasRESUMEN
The potent and selective inhibitor of ß-glucosidases, noeurostegine, was evaluated as an inhibitor of glucocerebrosidase (GCase) to give an IC(50) value of 0.4 µM, being 250- and 150-fold better than N-butyl and N-nonyl noeurostegine, respectively. The parent noeurostegine and its N-butyl and N-nonyl alkylated congeners were also tested as pharmacological chaperones against a N370S GCase mutant. Of these, only noeurostegine, was found to increase enzyme activity, which in potency was comparable to that previously reported for isofagomine.
Asunto(s)
Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/antagonistas & inhibidores , Nortropanos/síntesis química , Pruebas de Enzimas , Humanos , Concentración 50 Inhibidora , Nortropanos/química , Nortropanos/uso terapéuticoRESUMEN
The N-(E)-fluorobutenyl-3beta-(para-halo-phenyl)nortropanes 9-12 were synthesized as ligands of the dopamine transporter (DAT) for use as (18)F-labeled positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that compounds 9-12 have a high affinity for the DAT and are selective for the DAT compared to the serotonin and norepinephrine transporters. MicroPET imaging with [(18)F]9-[(18)F]11 in anesthetized cynomolgus monkeys showed high uptake in the putamen with lesser uptake in the caudate, but significant washout of the radiotracer was only observed for [(18)F]9. PET imaging with [(18)F]9 in an awake rhesus monkey showed high and nearly equal uptake in both the putamen and caudate with peak uptake achieved after 20 min followed by a leveling-off for about 10 min and then a steady washout and attainment of a quasi-equilibrium. During the time period 40-80 min postinjection of [(18)F]9, the ratio of uptake in the putamen and caudate vs cerebellum uptake was > or = 4.
Asunto(s)
Encéfalo/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Nortropanos/síntesis química , Radiofármacos/síntesis química , Animales , Unión Competitiva , Núcleo Caudado/metabolismo , Cerebelo/metabolismo , Radioisótopos de Flúor , Humanos , Ligandos , Macaca fascicularis , Nortropanos/química , Nortropanos/farmacocinética , Tomografía de Emisión de Positrones , Putamen/metabolismo , Radiofármacos/química , Radiofármacos/farmacocinética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A new, stable hemi-aminal nor-tropane christened noeurostegine was synthesised in 22 steps from levoglucosan and tested for inhibitory activity against glycoside hydrolases. Sweet almond and Thermotoga maritimabeta-glucosidases, coffee bean alpha-galactosidase, and Asp. oryzaebeta-galactosidase were inhibited in the low micromolar region but significant tightening of binding to K(i) 50 nM for almond beta-glucosidase was found to occur after pre-incubation. Yeast alpha-glucosidase and E. colibeta-galactosidase were not inhibited at 1 mM.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glicósido Hidrolasas/antagonistas & inhibidores , Nortropanos/síntesis química , Dominio Catalítico , Etilenos/química , Glicósido Hidrolasas/química , Glicósido Hidrolasas/metabolismo , Nortropanos/química , Nortropanos/farmacología , Alcaloides Solanáceos/química , Alcaloides Solanáceos/farmacología , Thermotoga maritima/enzimologíaRESUMEN
A series of 3-arylnortrop-2-enes and 3alpha-arylmethoxy-3beta-arylnortropanes were synthesized and evaluated for binding affinity at monoamine transporters. The 3-(3,4-dichlorophenyl)nortrop-2-ene (6e) exhibited high affinity for the SERT (K(i)=0.3 nM). The 3alpha-arylmethoxy-3beta-arylnortropanes were generally SERT selective with the 3alpha-(3.4-dichlorophenylmethoxy)-3betaphenylnortrop-2-ene (7c) possessing subnanomolar potency (K(i)=0.061 nM). However, 3alpha-(3,4-dichlorophenylmethoxy)-3beta-phenylnortrop-2-ene (7b) exhibited high affinity at all three transporters [(DAT K(i)=22 nM), (SERT K(i)=6 nM) and (NET K(i)=101 nM)].
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Nortropanos/química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Nortropanos/síntesis química , Nortropanos/metabolismoRESUMEN
A new dopamine transporter (DAT) ligand, (E)-N-(3-iodoprop-2-enyl)-2beta-carbofluoroethoxy-3beta-(4'-methyl-phenyl) nortropane (FE-PE2I, 6), derived from PE2I (1), was prepared and found to be a potent inhibitor of rodent DAT in vitro. Compound 6 was radiolabelled with fluorine-18 (t(1/2)=109.8 min) for PET studies in monkeys. In vivo PET measurements showed a regional distribution in brain that corresponds to the known distribution of DAT. This binding was specific, reversible and the kinetics of [(18)F]6 binding in brain were faster than for its lead compound, [(11)C]1. The possible presence of a hydroxymethyl-radiometabolite formed by oxidation in the 3beta-benzylic position of [(18)F]6 warrants further detailed evaluation of the metabolism of [(18)F]6. [(18)F]6 is a potential radioligand for imaging DATs in the human brain with PET.