RESUMEN
Hydroisoquinoline derivatives were prepared in moderate to good enantioselectivities via a bicyclic guanidine-catalyzed tandem isomerization intramolecular-Diels-Alder (IMDA) reaction of alkynes. With this synthetic method, the first enantioselective synthesis of (+)-alpha-yohimbine was completed in 9 steps from the IMDA products.
Asunto(s)
Guanidina/química , Yohimbina/síntesis química , Catálisis , Cristalografía por Rayos X , Reacción de Cicloadición , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estereoisomerismo , Yohimbina/químicaRESUMEN
Alstonine and serpentine are pentacyclic indoloquinolizidine alkaloids (referred to as "anhydronium bases") containing three contiguous stereocenters. Each possesses interesting biological activity, with alstonine being the major component of a plant-based remedy to treat psychosis and other nervous system disorders. This work describes the enantioselective total syntheses of these natural products with a cooperative hydrogen bonding/enamine-catalyzed Michael addition as the key step.
Asunto(s)
Aminas/química , Productos Biológicos/síntesis química , Yohimbina/síntesis química , Productos Biológicos/química , Catálisis , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Yohimbina/químicaRESUMEN
A strategy involving a Mannich-type multicomponent assembly process followed by a 1,3-dipolar cycloaddition has been developed for the rapid and efficient construction of parent heterocyclic scaffolds bearing indole and isoxazolidine rings. These key intermediates were then readily elaborated using well-established protocols for refunctionalization and cross-coupling to access a diverse 180-member library of novel pentacyclic and tetracyclic compounds related to the Yohimbine and Corynanthe alkaloids. Several other new multicomponent assembly processes were developed to access dihydro-ß-carboline-fused benzodiazepines, pyrimidinediones, and rutaecarpine derivatives.
Asunto(s)
Alcaloides/síntesis química , Alcaloides Indólicos/síntesis química , Yohimbina/síntesis química , Alcaloides/química , Técnicas Químicas Combinatorias , Ciclización , Alcaloides Indólicos/química , Indoles/química , Pausinystalia , Yohimbina/químicaRESUMEN
The yohimbinoid alkaloids continue to receive considerable attention from the synthetic community because of their interesting chemical structures and varied biological activity. Although there are several elegant syntheses of certain members of this group of alkaloids, a truly unified approach has yet to be developed. In short, general approaches to this compound class are hampered by a lack of complete control in setting the C(3) stereocentre at a late stage. Herein, we report that a functionalized hydrindanone enables a divergent strategy that builds on existing precedent to address this long-standing challenge. Utilizing an aminonitrile intermediate, the stereochemistry at C(3) of the yohimbinoid skeleton can be controlled effectively in a Pictet-Spengler reaction. We applied this approach to the first total syntheses of the C(3) epimeric natural products venenatine and alstovenine.
Asunto(s)
Alcaloides/síntesis química , Yohimbina/análogos & derivados , Yohimbina/química , Calor , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Tolueno , Yohimbina/síntesis químicaRESUMEN
The binolphosphoric acid-catalyzed Pictet-Spengler reaction of an N-(5-oxy-2,4-pentadienyl)tryptamine derivative with methyl 5-oxo-2-(phenylseleno)pentanoate leads to the tetrahydro-ß-carboline in a 92:8 enantiomeric ratio. This product is easily converted into the substrate for a stereoselective intramolecular Diels-Alder reaction of the type earlier reported by Jacobsen. These two key steps constitute the basis for a nine-step total synthesis of (+)-yohimbine from tryptamine. A similar asymmetric Pictet-Spengler reaction was applied to the synthesis of an intermediate in the recent total synthesis of corynantheidine by Sato.
Asunto(s)
Triptaminas/química , Yohimbina/química , Yohimbina/síntesis química , Catálisis , Ciclización , Estructura Molecular , EstereoisomerismoRESUMEN
The total synthesis of (+)-yohimbine was achieved in 11 steps and 14% overall yield. The absolute configuration was established through a highly enantioselective thiourea-catalyzed acyl-Pictet-Spengler reaction, and the remaining 4 stereocenters were set simultaneously in a substrate-controlled intramolecular Diels-Alder reaction.
Asunto(s)
Yohimbina/síntesis química , Catálisis , Ciclización , Estructura Molecular , Estereoisomerismo , Yohimbina/químicaRESUMEN
A series of yohimbine derivatives was synthesized and evaluated for binding affinity at the human alpha(2C)-adrenergic receptors expressed in Chinese hamster ovary cells. It has been found that compound 5 shows a higher affinity for alpha(2C)-AR than the parent compound yohimbine 1, thereby illustrating that the nature of the linkers affect binding potencies on these receptors.
Asunto(s)
Receptores Adrenérgicos alfa 2/efectos de los fármacos , Yohimbina/síntesis química , Yohimbina/farmacología , Animales , Células CHO , Cricetinae , Humanos , Ratones , Unión Proteica , Receptores Adrenérgicos alfa 2/metabolismo , Yohimbina/metabolismoRESUMEN
A series of yohimbine dimers was prepared and evaluated at the human alpha2a- and alpha2b-adrenergic receptors (ARs) expressed in Chinese hamster ovary (CHO) cells. All dimers display higher binding selectivities for alpha2a versus alpha2b subtype than yohimbine, and four compounds (3d, 3e, 3g and 3i) represent the most potent and alpha2a versus alpha2b-AR selective ligands identified so far.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos alfa/farmacología , Yohimbina/farmacología , Antagonistas Adrenérgicos alfa/síntesis química , Antagonistas Adrenérgicos alfa/química , Animales , Unión Competitiva , Células CHO , Cricetinae , Dimerización , Humanos , Receptores Adrenérgicos alfa 2/genética , Relación Estructura-Actividad , Transfección , Yohimbina/síntesis química , Yohimbina/químicaRESUMEN
[125I]17alpha-hydroxy-20alpha-yohimban-16beta-(N-4-p6 hydroxyphenethyl)carboxamide or [125I]rauwolscine-OHPC, a new radioiodinated probe derived from rauwolscine was synthesized and its binding characteristics investigated on sections of the mouse caudate putamen. [125I]rauwolscine-OHPC binding was saturable and revealed interaction with a single class of binding sites (KD= 0.171 nM, Bmax = 3082 pCi/mg of tissue). The kinetically derived affinity was in close agreement with the affinity evaluated by saturation experiments: k(-1)/k(+1)(0.0403 min(-1)/114 10(6) M(-1) min(-1))=0.35 nM. Competition studies revealed interaction with one single class of binding sites for each of the twelve compounds tested. The rank of potency suggested an interaction with alpha2 adrenoceptors (atipamezole > or = RX 821002 > yohimbine > (-)epinephrine). Moreover, the good affinity of [125I] rauwolscine-OHPC binding sites for spiroxatrine, yohimbine, WB 4101, the relatively good affinity for prazosin (Ki =37.4 nM) and the affinity ratio prazosin/oxymetazoline (37.4/43.4=0.86) were consistent with an alpha2C selective labelling of [125I]rauwolscine-OHPC. The distribution of [125I]rauwolscine-OHPC binding sites in mouse brain was characterized by autoradiography. The density of binding sites was high in the islands of Calleja, accumbens nucleus, caudate putamen and olfactory tubercles, moderate in the hippocampus, amygdala and anterodorsal nucleus of the thalamus. These findings demonstrated that [125I]rauwolscine-OHPC is a useful radioiodinated probe to label alpha2C adrenoceptors in mouse brain.
Asunto(s)
Encéfalo/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Yohimbina/análogos & derivados , Animales , Autorradiografía , Sitios de Unión , Unión Competitiva , Núcleo Caudado/metabolismo , Epinefrina/farmacología , Radioisótopos de Yodo , Cinética , Masculino , Ratones , Ratones Endogámicos , Estructura Molecular , Especificidad de Órganos , Oximetazolina/farmacología , Prazosina/farmacología , Putamen/metabolismo , Receptores Adrenérgicos alfa 2/análisis , Yohimbina/síntesis química , Yohimbina/farmacocinética , Yohimbina/farmacologíaRESUMEN
We designed and evaluated a new class of molecules, nitrosylated alpha-adrenergic receptor antagonists, as potential agents for the treatment of impotence. In in vitro studies with human and rabbit corpus cavernosum strips in organ chambers, the alpha-adrenergic receptor antagonists (alpha-ARAs) moxisylyte and yohimbine and their corresponding nitrosylated compounds, SNO-moxisylyte (NMI-221) and SNO-yohimbine (NMI-187), concentration-dependently relaxed endothelin-induced contraction. The nitrosylated compounds were significantly more potent than the parent alpha-ARA. In human tissues, the specific phosphodiesterase type 5 inhibitor zaprinast potentiated the relaxing effects of the nitrosylated compounds. Only nitrosylated compounds induced accumulation of cyclic GMP in rabbit corpus cavernosum strips. Yohimbine and NMI-187 demonstrated a potent alpha2-blocking activity, with no significant differences in pA2 values (8.9 versus 8.2, respectively). Moxisylyte and NMI-221 showed moderate potency in antagonizing phenylephrine contraction, with comparable pA2 values for both molecules (6.5 versus 6.6, respectively). alpha-Adrenergic receptor-binding studies showed similar binding affinities for the alpha-ARA and their corresponding nitrosylated compounds. In vivo, intracavernosal injection of nitrosylated molecules caused greater increases in intracavernosal pressure (NMI-221 versus moxisylyte) that were more long lasting than those of moxisylyte or yohimbine. There were no significant differences between nitrosylated and non-nitrosylated compounds in the magnitude of systemic mean arterial pressure decrease after intracavernosal injection. alpha-ARA and the nitrosylated compounds showed no pain-inducing activity as evaluated with the paw-lick model in mice. In summary, nitrosylated alpha-ARA have the dual functionalities of nitric oxide donors and alpha-ARA. These drugs induced penile erection in animals, suggesting their possible therapeutic value as agents for the local pharmacological treatment of impotence.
Asunto(s)
Antagonistas Adrenérgicos alfa/síntesis química , Disfunción Eréctil/tratamiento farmacológico , Moxisilita/análogos & derivados , Compuestos Nitrosos/síntesis química , Compuestos Nitrosos/farmacología , Vasodilatadores/síntesis química , Yohimbina/análogos & derivados , Antagonistas Adrenérgicos alfa/metabolismo , Antagonistas Adrenérgicos alfa/farmacología , Animales , GMP Cíclico/metabolismo , Diseño de Fármacos , Endotelinas/farmacología , Humanos , Técnicas In Vitro , Masculino , Membranas , Ratones , Moxisilita/síntesis química , Moxisilita/metabolismo , Moxisilita/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Pene/efectos de los fármacos , Pene/metabolismo , Pene/fisiología , Fenilefrina/farmacología , Conejos , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Vasodilatadores/metabolismo , Vasodilatadores/farmacología , Yohimbina/síntesis química , Yohimbina/metabolismo , Yohimbina/farmacologíaRESUMEN
[2S*-(2 beta,3 alpha,6 alpha,12b beta)]-Methyl 3-acetyl-1,2,3,4,6,7,12,12b-octahydro-6-methoxycarbonyl-indolo+ ++[2,3-a] quinolizine-3-ethanoate, C22H26N2O5, M(r) = 398.46, orthorhombic, P2(1)2(1)2(1), a = 9.463 (2), b = 11.251 (3), c = 18.871 (6) A, V = 2009.2 (9) A3, Z = 4, Dx = 1.32 g cm-3 (178 K), lambda(Mo K alpha) = 0.7107 A, mu = 0.8762 cm-1, F(000) = 848, T = 178 K, R = 0.0536 for 1673 reflections [Fo > or = 6 sigma (Fo)]. Molecules are hydrogen bonded along the 2(1)-screw axis parallel to a. The hydrogen-bond geometric parameters for N12-H12...O19 (related by 0.5 + x, 1.5 - y, 1 - z) are N...O 2.986 (6), H...O 2.30 (5) A, N-H...O 161 (5) degrees. The C and D rings are trans fused with ring-junction torsion angles of -39.6 (5) and 63.8 (5) degrees for C12a-C12b-N5-C6 and C1-C12b-N5-C4, respectively. The conformation of the C ring is half chair with N5 and C6 -0.168 (4) and 0.552 (5) A, respectively, out of the plane defined by the remaining four atoms of the ring. The D ring is in the chair conformation.
Asunto(s)
Alcaloides de Triptamina Secologanina , Yohimbina/análogos & derivados , Cristalización , Enlace de Hidrógeno , Conformación Molecular , Estructura Molecular , Difracción de Rayos X , Yohimbina/síntesis química , Yohimbina/químicaRESUMEN
We have provided a detailed protocol for the synthesis of a yohimbine-agarose matrix that has been shown to be effective for isolation of the alpha 2A-adrenergic receptor from human platelet and purification of the alpha 2A-adrenergic receptor to apparent homogeneity from porcine brain cortex using chromatography on only two sequential yohimbine-agarose columns. In addition, this affinity matrix also interacts with alpha 2 receptors of the alpha 2B subtype extracted from cultured NG108-15 cells. Finally, this affinity matrix has proven useful for monitoring posttranslational modifications of the receptor in digitonin extracts of metabolically labeled cells. Thus, this affinity matrix can be exploited for the purification of multiple alpha 2-adrenergic receptor subtypes on both a macro- and microscale and should be of value to any laboratory exploring the molecular basis for alpha 2-adrenergic functions.
Asunto(s)
Plaquetas/metabolismo , Receptores Adrenérgicos alfa/aislamiento & purificación , Sefarosa/análogos & derivados , Yohimbina/análogos & derivados , Agonistas alfa-Adrenérgicos/metabolismo , Fraccionamiento Celular/métodos , Cromatografía de Afinidad/métodos , Digitonina , Humanos , Indicadores y Reactivos , Ensayo de Unión Radioligante/métodos , Receptores Adrenérgicos alfa/análisis , Receptores Adrenérgicos alfa/metabolismo , Sefarosa/síntesis química , Tritio , Yohimbina/sangre , Yohimbina/síntesis químicaRESUMEN
Methyl [4aS*-(4 alpha,4a beta,7 beta,13b beta,14a beta)]-7,8,13,13b,14,14a- hexahydro-4-methyl-5-oxo-4H-indolo-[2,3-a]pyrano[3,4-g]qu inolizine-7-carboxylate acetone solvate, C22H22N2O4.C3H6O, Mr = 424.50, triclinic, P1, a = 9.9955(13), b = 10.8523(14), c = 11.9352(14) A, alpha = 63.189(9), beta = 72.286(9), gamma = 72.901(10) degrees, V = 1081.8(2) A3, Z = 2, Dx = 1.30 g cm-3(198K), mu = 0.8554 cm-1, Mo K alpha radiation, lambda = 0.7107 A, F(000) = 452, T = 198 K, R = 0.0435 for 3842 reflections, FO greater than or equal to 4 sigma (FO). The acetone solvent is hydrogen bonded to the indole NH group with relevant parameters: N13...O1A 2.982(2), H13...O1A 2.10(2) A, N--H...O 164(2) degrees. The conformation at the C and D ring junction is quasi-cis [relevant torsion angles are C7--N6--C13B--C13A 9.4(2) degrees and C5--N6--C13B--C14 46.7(2) degrees] while the conformation at the D and E ring junction is cis [relevant torsion angles are 37.8(2) degrees for C5--C4A--C14A--C14 and 41.3(2) degrees for C4--C4A--C14A--C1].
Asunto(s)
Alcaloides de Triptamina Secologanina , Yohimbina/análogos & derivados , Estructura Molecular , Difracción de Rayos X , Yohimbina/síntesis química , Yohimbina/químicaRESUMEN
The selective alpha 2-adrenergic receptor antagonist rauwolscine was structurally modified to yield a series of arylamine carboxamide derivatives, which were investigated as potential molecular probes for the localization and structural characterization of alpha 2-adrenergic receptors. The arylamine carboxamides differ in the number of carbon atoms separating the reactive phenyl moiety from the fused ring structure of the parent compound, rauwolscine carboxylate. Competitive inhibition studies with [3H]rauwolscine in rat kidney membranes indicate that the affinity for the carboxamide derivatives is inversely related to the length of the carbon spacer arm with rauwolscine 4-aminophenyl carboxamide (zero carbon spacer arm; rau-AMPC) exhibiting the highest affinity (Kd = 2.3 +/- 0.2 nM). Radioiodination of rau-AMPC yields a ligand, 125I-rau-AMPC, which binds to rat kidney alpha 2-adrenergic receptors with high affinity, as determined by both kinetic analysis (Kd = k2/k1 = 0.016 min-1/2.1 X 10(7) M-1 min-1 = 0.76 nM) and equilibrium binding studies (Kd = 0.78 +/- 0.16 nM). 125I-rau-AMPC was quantitatively converted to the photolabile arylazide derivative 17 alpha-hydroxy-20 alpha-yohimban-16 beta-(N-4-azido-3-[125I]iodophenyl) carboxamide (125I-rau-AZPC). In a partially purified receptor preparation from porcine brain, this compound photolabels a major (Mr = 62,000) peptide. The labeling of this peptide is inhibited by adrenergic agonists and antagonists with a rank order of potency consistent with an alpha 2-adrenergic receptor binding site. Both 125I-rau-AMPC and the photolabile arylazide derivative, 125I-rau-AZPC, should prove useful as molecular probes for the structural and biochemical characterization of alpha 2-adrenergic receptors.