RESUMEN
We describe the synthesis of 1,1'- and 2,2'-bicarbazoles by oxidative homocoupling of 2- and 1-hydroxycarbazoles. The oxidative coupling using catalytic amounts of F16 PcFe can be applied to both groups of substrates. Although F16 PcFe generally provides the best yields for the synthesis of 1,1'-bicarbazoles, di-tert-butyl peroxide affords better results for the 2,2'-bicarbazoles. In our study, we have achieved the first syntheses of the biscarbalexines A-C, bisglybomine B, 2,2'-dihydroxy-7,7'-dimethoxy-3,3'-dimethyl-1,1'-bicarbazole, bispyrayafoline C, and bisisomahanine. The iron-catalyzed coupling of koenigine led to an improved synthesis of 8,8''-biskoenigine and afforded an unprecedented decacylic product. Oxidative coupling of 1-hydroxycarbazoles led to bisclausenol, and to the first total syntheses of bismurrayafoline B and D.
RESUMEN
We describe the total synthesis of methylene-bridged biscarbazole alkaloids by using a late-stage Ullmann-type coupling of fully functionalised carbazole subunits. The carbazole derivatives were synthesised via a sequence of palladium(0)- and palladium(II)-catalysed coupling reactions. Our approach has provided bismurrayafoline-A, bismurrayafolinol, chrestifolinesâ B-D, and the first total synthesis of murrastifoline-C and murrafoline-E.
Asunto(s)
Alcaloides/síntesis química , Carbazoles/química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Paladio/química , Alcaloides/química , Carbazoles/síntesis química , Catálisis , Compuestos Heterocíclicos de 4 o más Anillos/química , Estructura Molecular , EstereoisomerismoRESUMEN
We describe a regioselective synthesis of 4- or 5-substituted carbazoles by oxidative cyclisation of meta-oxygen-substituted N-phenylanilines. Using the regiodirecting effect of a pivaloyloxy group, we prepared 4-hydroxycarbazole, a precursor for the enantiospecific synthesis of the ß-adrenoreceptor antagonists (-)-(S)-carazolol (5) and (-)-(S)-carvedilol (6). Regioselective palladium(II)-catalysed cyclisation of different diarylamines led to total synthesis of glycoborine (7) and the first total syntheses of the phytoalexin carbalexin A (8), glybomine A (9) and glybomine B (10). For glybomine B (10), a 5-hydroxycarbazole was converted into the corresponding triflate and utilized for introduction of a prenyl substituent.
Asunto(s)
Carbazoles/síntesis química , Química Farmacéutica/métodos , Carvedilol , Catálisis , Ciclización , Modelos Químicos , Oxidación-Reducción , Paladio/química , Propanolaminas/síntesis química , Sesquiterpenos/síntesis química , Espectrometría de Masa por Ionización de Electrospray , FitoalexinasRESUMEN
We describe efficient synthetic routes to murrayamine A (mukoenine C), O-methylmurrayamine A, mahanine, O-methylmahanine, and murrayamine D and the first total syntheses of murrayamine E, I, and K. Key steps are a palladium-catalyzed construction of the carbazole framework and an annulation of the pyran ring, which is either catalyzed by phenylboronic acid or promoted by a Lewis acid.
Asunto(s)
Alcaloides/química , Carbazoles/química , Carbazoles/síntesis química , Ácidos de Lewis/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
The boronic acid-catalyzed annulation of citral opens up a short route to oxygenated cyclized monoterpenoid pyranocarbazole alkaloids. Thus, murrayamine-D is available in only three steps and 55% overall yield from the corresponding carbazole precursor.
Asunto(s)
Alcaloides/síntesis química , Ácidos Borónicos/química , Carbazoles/química , Carbazoles/síntesis química , Catálisis , Ciclización , Estructura Molecular , Piranos , EstereoisomerismoRESUMEN
The DIBAL-H promoted reductive pyran ring opening of dialkylpyrano[3,2-a]carbazoles provides a direct access to a broad range of prenyl- and geranyl-substituted carbazoles. Formation of a pyran ring followed by reductive ring opening represents a new method for the introduction of prenyl and geranyl groups. In the course of the present work, we achieved the first total syntheses of the following eight carbazole alkaloids: clauraila-E, 7-hydroxyheptaphylline, 7-methoxyheptaphylline, mukoenine-B (clausenatine-A), mukoenine-A (girinimbilol), mahanimbinol (mahanimbilol), euchrestine-A, and isomurrayafoline-B.
Asunto(s)
Alcaloides/síntesis química , Carbazoles/síntesis química , Compuestos Organometálicos/química , Alcaloides/química , Carbazoles/química , Cristalografía por Rayos X , Estructura Molecular , Prenilación , Piranos/química , Sustancias Reductoras/química , EstereoisomerismoRESUMEN
We describe an efficient synthesis of the methylene-bridged biscarbazole alkaloids bismurrayafoline-A, bismurrayafolinol and chrestifoline B-D using an Ullmann-type coupling at the benzylic position.
Asunto(s)
Alcaloides/química , Carbazoles/síntesis química , Química Orgánica/métodos , Alcaloides/síntesis química , Carbazoles/química , Nitrobenzoatos/químicaRESUMEN
Seven naturally occurring pyranocarbazole alkaloids (pyrayafoline A-E, O-methylmurrayamine A and O-methylmahanine) have been obtained by total synthesis using a palladium(II)-catalysed oxidative cyclisation of a diarylamine to an orthogonally diprotected 2,7-dihydroxycarbazole as key step.
Asunto(s)
Alcaloides/síntesis química , Carbazoles/síntesis química , Química Orgánica/métodos , Paladio/química , Piranos/síntesis química , Alcaloides/química , Carbazoles/química , Catálisis , Conformación Molecular , Piranos/químicaRESUMEN
The synthesis of seven pyrano[3,2-a]carbazole alkaloids has been achieved using their putative biogenetic precursor 2-hydroxy-6-methylcarbazole as key intermediate.
Asunto(s)
Alcaloides/síntesis química , Carbazoles/química , Alcaloides/química , Carbazoles/síntesis química , Estructura MolecularRESUMEN
We describe the regioselective prenylation of 3-bromocarbazole by palladium(0)-catalysed cross coupling with a prenylstannane or a prenylboronate. The procedure is applied to the synthesis of precursors for biologically active carbazole alkaloids.
Asunto(s)
Carbazoles/química , Compuestos Organometálicos/química , Paladio/química , Carbazoles/síntesis química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
Inherited cardiomyopathies are common cardiac diseases worldwide, leading in the late stage to heart failure and death. The most promising treatments against these diseases are small molecules directly modulating the force produced by ß-cardiac myosin, the molecular motor driving heart contraction. Omecamtiv mecarbil and Mavacamten are two such molecules that completed phase 3 clinical trials, and the inhibitor Mavacamten is now approved by the FDA. In contrast to Mavacamten, Omecamtiv mecarbil acts as an activator of cardiac contractility. Here, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All-atom molecular dynamics simulations reveal how these molecules produce distinct effects in motor allostery thus impacting force production in opposite way. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.
Asunto(s)
Simulación de Dinámica Molecular , Contracción Miocárdica , Urea , Contracción Miocárdica/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Urea/análogos & derivados , Urea/farmacología , Urea/química , Miosinas Cardíacas/metabolismo , Miosinas Cardíacas/química , Miosinas Cardíacas/genética , Miosinas Ventriculares/metabolismo , Miosinas Ventriculares/química , Miosinas Ventriculares/genética , Animales , Bencilaminas , Uracilo/análogos & derivadosRESUMEN
We have developed a highly efficient route to 2-hydroxy-3-methylcarbazole (1) via a palladium-catalyzed construction of the carbazole skeleton. Using 1 as relay compound, different methods for annulations of pyran rings by reaction with terpenoid building blocks have been tested. The Lewis acid promoted reaction of 1 with prenal (21) opened up an efficient route to girinimbine (3) and the corresponding reaction with citral (25) afforded mahanimbine (5). Oxidation of compounds 3 and 5 provided murrayacine (4) and murrayacinine (6). Following the biogenetic proposal, mahanimbine (5) has been exploited for efficient biomimetic syntheses of the cyclized monoterpenoid pyrano[3,2-a]carbazole alkaloids cyclomahanimbine (7), mahanimbidine (8) and bicyclomahanimbine (9). The interconversions of 5, 7, 8 and 9 are described and mechanistic implications are discussed. Structural assignments are unambiguously verified by X-ray crystal structure determinations. Moreover, cyclomahanimbine (7) was transformed into murrayazolinine (10) and exozoline (11).
Asunto(s)
Carbazoles/química , Carbazoles/síntesis química , Ácidos de Lewis/química , Monoterpenos/síntesis química , Piranos/síntesis química , Biomimética , Cristalografía por Rayos X , Ciclización , Estructura Molecular , Monoterpenos/química , Oxidación-Reducción , Paladio/química , Piranos/químicaRESUMEN
A variety of cholestan-3ß-ol derivatives, which are oxygenated at different positions of the steroid ring system, were prepared and tested for their inhibition of the Mycobacterium tuberculosis H37Rv strain. Several compounds showed significant antitubercular activities with MIC90 values in the range 4-8 µM and low or non-detectable toxicity against mammalian cells.
Asunto(s)
Antituberculosos/farmacología , Colestanoles/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Colestanoles/síntesis química , Colestanoles/química , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/crecimiento & desarrollo , Oxidación-Reducción , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Using 3ß-hydroxychol-5-en-24-oic acid (4) as starting material, the diastereoisomeric allylic alcohols (24E)-26-hydroxydesmosterol (2) and (24Z)-26-hydroxydesmosterol (3) have been synthesised in six steps with 67% and 12% overall yield, respectively. Both of these isomers are found in newborn mouse brain where sterol synthesis is high. Unlike desmosterol (1), neither of these isomers is a ligand to the liver x receptors and thus represents a novel biological deactivation mechanism avoiding cholesterol synthesis.
Asunto(s)
Desmosterol/análogos & derivados , Desmosterol/química , Animales , Encéfalo/metabolismo , Cristalografía por Rayos X , Desmosterol/síntesis química , Isomerismo , Receptores X del Hígado , Ratones , Conformación Molecular , Receptores Nucleares Huérfanos/química , Receptores Nucleares Huérfanos/metabolismoRESUMEN
Inherited cardiomyopathies are amongst the most common cardiac diseases worldwide, leading in the late-stage to heart failure and death. The most promising treatments against these diseases are small-molecules directly modulating the force produced by ß-cardiac myosin, the molecular motor driving heart contraction. Two of these molecules that produce antagonistic effects on cardiac contractility have completed clinical phase 3 trials: the activator Omecamtiv mecarbil and the inhibitor Mavacamten. In this work, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All atoms molecular dynamics simulations reveal how these molecules can have antagonistic impact on the allostery of the motor by comparing ß-cardiac myosin in the apo form or bound to Omecamtiv mecarbil or Mavacamten. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.
RESUMEN
A stereoselective synthesis of (25S)-Δ(1)-, (25S)-Δ(1,4)-, (25S)-Δ(1,7)-, (25S)-Δ(8(14))-, (25S)-Δ(4,6,8(14))-dafachronic acid, methyl (25S)-Δ(1,4)-dafachronate and (25S)-5α-hydroxy-3,6-dioxocholest-7-en-26-oic acid is described. (25S)-Δ(1,4)-Dafachronic acid and its methyl ester are natural products isolated from corals and have been obtained by synthesis for the first time. (25S)-5α-Hydroxy-3,6-dioxocholest-7-en-26-oic acid represents a promising synthetic precursor for cytotoxic marine steroids.
Asunto(s)
Antozoos/química , Caenorhabditis elegans/efectos de los fármacos , Colestenos/síntesis química , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/crecimiento & desarrollo , Proteínas de Caenorhabditis elegans/genética , Colestenos/farmacología , Relación Dosis-Respuesta a Droga , Ésteres/síntesis química , Ésteres/farmacología , Larva/efectos de los fármacos , Larva/genética , Larva/crecimiento & desarrollo , Estructura Molecular , Receptores Citoplasmáticos y Nucleares/deficiencia , Receptores Citoplasmáticos y Nucleares/genética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We describe an efficient total synthesis of the sesquiterpenes (±)-ß-isocomene and (±)-isocomene using a Lewis acid-promoted [3 + 2] cycloaddition of allyl-tert-butyldiphenylsilane as the key-step.
RESUMEN
We describe the stereoselective transformation of diosgenin (4a) to (25R)-Delta(4)-dafachronic acid (1a),(25R)-Delta(7)-dafachronic acid (2a), and (25R)-cholestenoic acid (3a), which represent potential ligands forthe hormonal receptor DAF-12 in Caenorhabditis elegans. Key-steps of our synthetic approach are amodified Clemmensen reduction of diosgenin (4a) and a double bond shift from the 5,6- to the 7,8-position. In the 25R-series, the Delta(7)-dafachronic acid 2a exhibits the highest hormonal activity.
Asunto(s)
Proteínas de Caenorhabditis elegans/efectos de los fármacos , Colestenos/síntesis química , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Animales , Caenorhabditis elegans , Colestenos/farmacología , Diosgenina/química , Ligandos , Relación Estructura-ActividadAsunto(s)
Alcaloides/síntesis química , Alcaloides/aislamiento & purificación , Carbazoles/química , Alcaloides/química , Alcaloides/farmacología , Benzoquinonas/síntesis química , Carbazoles/síntesis química , Carbazoles/farmacología , Elipticinas/síntesis química , Furanos/síntesis química , Alcaloides Indólicos/síntesis química , Estructura Molecular , Fenómenos Químicos Orgánicos , Pirroles/síntesis química , Quinonas/síntesis químicaRESUMEN
Upon starvation or overcrowding, Caenorhabditis elegans interrupts its reproductive cycle and forms a specialised larva called dauer (enduring). This process is regulated by TGF-beta and insulin-signalling pathways and is connected with the control of life span through the insulin pathway components DAF-2 and DAF-16. We found that replacing cholesterol with its methylated metabolite lophenol induced worms to form dauer larvae in the presence of food and low population density. Our data indicate that methylated sterols do not actively induce the dauer formation but rather that the reproductive growth requires a cholesterol-derived hormone that cannot be produced from methylated sterols. Using the effect of lophenol on growth, we have partially purified activity, named gamravali, which promotes the reproduction. In addition, the effect of lophenol allowed us to determine the role of sterols during dauer larva formation and longevity. In the absence of gamravali, the nuclear hormone receptor DAF-12 is activated and thereby initiates the dauer formation program. Active DAF-12 triggers in neurons the nuclear import of DAF-16, a forkhead domain transcription factor that contributes to dauer differentiation. This hormonal control of DAF-16 activation is, however, independent of insulin signalling and has no influence on life span.