RESUMEN
A mild and atom-economic rhenium(V)-catalyzed stereoselective synthesis of ß-D-digitoxosides from 6-deoxy-D-allals has been described. This ß-selective glycosylation was achieved probably because of the formation of corresponding α-digitoxosides disfavored by 1,3-diaxial interaction. In addition, this method has been successfully applied to the synthesis of digitoxin trisaccharide glycal for the direct synthesis of digitoxin and C1'-epi-digitoxin.
Asunto(s)
Digitoxina/síntesis química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Catálisis , Digitoxina/análogos & derivados , Digitoxina/química , Datos de Secuencia Molecular , EstereoisomerismoRESUMEN
The cardiac glycoside natural product digitoxin was selectively glycosylated at one of its five hydroxyl groups using a borinic acid derived catalyst. This method provided access to the glycosylation pattern characteristic of a subclass of natural products from Digitalis purpurea. Variation of the glycosyl donor was tolerated, enabling the synthesis of novel cardiac glycoside analogs from readily available materials.
Asunto(s)
Glicósidos Cardíacos/síntesis química , Digitoxina , Ácidos Borínicos/química , Glicósidos Cardíacos/química , Catálisis , Digitalis/química , Digitoxina/análogos & derivados , Digitoxina/síntesis química , Digitoxina/química , Glicosilación , Estructura Molecular , EstereoisomerismoRESUMEN
Sweet'n low in stereo: A Wharton reaction was employed along with a diastereoselective palladium-catalyzed glycosylation and other post-glycosylation transformations to synthesize digitoxin analogues. Cytotoxic evaluation against a panel of cancer cell lines uncovered the stereochemical and substitutional limits of the C3'/C4'-hydroxy functionality in digitoxin monosaccharide.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Digitoxigenina/química , Digitoxigenina/farmacología , Digitoxina/análogos & derivados , Digitoxina/farmacología , Antineoplásicos/síntesis química , Cardiotónicos/síntesis química , Cardiotónicos/química , Cardiotónicos/farmacología , Catálisis , Línea Celular Tumoral , Digitoxigenina/síntesis química , Digitoxina/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Glicosilación , Humanos , Neoplasias/tratamiento farmacológico , Paladio/química , EstereoisomerismoRESUMEN
Digitoxin, a clinically important cardiac trisaccharide, was assembled efficiently from digitoxigenin and 3,4-di-O-tert-butyldiphenylsilyl-d-digitoxosyl o-cyclopropylethynylbenzoate in 9 steps and 52% overall yield via alternate glycosylation and protecting group manipulation. The present synthesis showcases the advantage of the gold(I)-catalyzed glycosylation protocol in the synthesis of glycoconjugates containing acid-labile 2-deoxysugar linkages.
Asunto(s)
Benzoatos/química , Digitoxina/síntesis química , Glicósidos/química , Oro/química , Catálisis , Digitoxina/química , Conformación MolecularRESUMEN
To address the medicinal chemist's need for new synthetic methods for the preparation of unnatural carbohydrates, a new de novo method for carbohydrate synthesis has been developed. These routes use a palladium catalyzed glycosylation reaction to stereoselectively control the anomeric center and subsequent diastereoselective post glycosylation to install the remaining sugar stereocenters. The utility of this method was demonstrated by the syntheses and biological evaluation of several digitoxin oligosaccharide analogues.
Asunto(s)
Antineoplásicos/síntesis química , Digitoxina/síntesis química , Oligosacáridos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Química Farmacéutica , Digitoxina/análogos & derivados , Digitoxina/farmacología , Humanos , Estructura Molecular , Oligosacáridos/química , Oligosacáridos/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A highly enantioselective and straightforward route to trisaccharide natural products digoxose and digitoxin has been developed. Key to this approach is the iterative application of the palladium-catalyzed glycosylation reaction, reductive 1,3-transposition, diastereoselective dihydroxylation, and regioselective protection. The first total synthesis of natural product digoxose was accomplished in 19 total steps from achiral 2-acylfuran, and digitoxin was fashioned in 15 steps starting from digitoxigenin 2 and pyranone 8beta. This flexible synthetic strategy also allows for the preparation of mono- and disaccharide analogues of digoxose and digitoxin.
Asunto(s)
Digitoxina/síntesis química , Oxígeno/química , Trisacáridos/síntesis química , Conformación de Carbohidratos , Catálisis , Digitoxina/química , Disacáridos/química , Glucosa/química , Glicosilación , Paladio/química , Estereoisomerismo , Trisacáridos/químicaRESUMEN
A convergent and stereocontrolled route to trisaccharide natural product digitoxin has been developed. The route is amenable to the preparation of both the digitoxigen mono- and bisdigitoxoside. This route featured the iterative application of the palladium-catalyzed glycosylation reaction, reductive 1,3-transposition, diastereoselective dihydroxylation, and regioselective protection. The natural product digitoxin was fashioned in 15 steps starting from digitoxigenin 2 and pyranone 8a or 18 steps from achiral acylfuran.
Asunto(s)
Digitoxigenina/química , Digitoxina/análogos & derivados , Digitoxina/síntesis química , Paladio/química , Secuencia de Carbohidratos , Glicosilación , Datos de Secuencia Molecular , EstereoisomerismoRESUMEN
Glycosylated natural products are reliable platforms for the development of many front-line drugs, yet our understanding of the relationship between attached sugars and biological activity is limited by the availability of convenient glycosylation methods. When a universal chemical glycosylation method that employs reducing sugars and requires no protection or activation is used, the glycorandomization of digitoxin leads to analogs that display significantly enhanced potency and tumor specificity and suggests a divergent mechanistic relationship between cardiac glycoside-induced cytotoxicity and Na+/K+-ATPase inhibition. This report highlights the remarkable advantages of glycorandomization as a powerful tool in glycobiology and drug discovery.
Asunto(s)
Antineoplásicos/química , Glicósidos Cardíacos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Glicósidos Cardíacos/síntesis química , Glicósidos Cardíacos/farmacología , Línea Celular Tumoral , Digitoxina/análogos & derivados , Digitoxina/síntesis química , Digitoxina/química , Digitoxina/farmacología , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glicosilación , Humanos , Hidrólisis , Ratones , Estructura Molecular , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidoresRESUMEN
All natural cardiac glycosides (CG) have a hydroxyl (OH) group attached to carbon 14 (C 14) of the steroid nucleus which has been considered important for their pharmacological action. To investigate the relation between chemical structure and biological activity of CG, we studied the cardiac effects of a semisynthetic derivative if gluco-digitoxigenin that lacks the C 14 hydroxyl group; the compound was named Dig-3 and corresponds to the number of a series of semisynthetic glycosides being studied. On the failing heart of the Starling's heart-lung preparation Dig-3 reverts experimental cardiac failure. Electrophysiological experiments in anesthetized dogs (morphine chloralose) have shown that Dig-3 shortens the functional refractory period of the ordinary atrial myocardium (OAM), and lengthens that of the specialized atrial tissue (SAT). The basal excitability is reduced in both tissues, however OAM is more susceptible to Dig-3 action. The conduction velocity of impulses in SAT diminishes 50% with one tenth of the lethal dose (LD) of Dig-3 whereas in the OAM, an equivalent decrease is achieved with 60% of LD. A-V dissociation induced by the infusion of toxic doses of Dig-3 reverted to sinus rhythm in about 6 min after the administration was stopped. We conclude that the presence of the OH group attached to C 14 of digitalis molecule does not constitute a structural requirement for the preservation of its inotropic and electrophysiological actions on the heart, although its potency is greatly diminished.
Asunto(s)
Digitoxina/análogos & derivados , Contracción Miocárdica/efectos de los fármacos , Animales , Digitoxina/síntesis química , Digitoxina/farmacología , Digitoxina/toxicidad , Perros , Femenino , Atrios Cardíacos/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Masculino , Ouabaína/farmacología , Periodo Refractario Electrofisiológico/efectos de los fármacos , Estimulación Química , Relación Estructura-Actividad , Fibrilación Ventricular/inducido químicamenteRESUMEN
Cardenolide glucuronides are synthesized in the following way: firstly cardenolide glucosides are prepared by the reaction with acetobromglucose; secondly the hydroxymethyl group of the glucose moiety is oxydized in presence of a platinum catalyst to the carboxyl group of the final glucuronic acid. Glucuronides of the following cardenolides are prepared and described: digoxin, digoxigenin, digitoxin, digitoxigenin-monodigitoxoside, digitoxigenin, and 3-epi-digitoxigenin. Sulphates of digoxigenin, digitoxigenin, and 3-epi-digitoxigenin are prepared by direct reaction of these cardenolides with chlorosulphonic acid in pyridine. The assumed structure of some conjugates has been confirmed by n.m.r. spectroscopy. A high water solubility (6.7-65.1 g/l), a minute chloroform solubility (0.0002-0.0005 g/l), and a low octanol/polar nature of these compounds. Inotropic or toxic cardiac activities of the conjugates are examined on isolated guinea pig papillary muscles and by the Hatcher method on cats. Conjugates with at least one digitoxose show cardioactivities comparable to digoxin or digitoxin. In contrast to that the conjugated genins indicate decreased activities which are at least one-tenth of the potency of the unconjugated glycosides.