RESUMEN
An unusual reaction is described, involving a formal intramolecular nucleophilic substitution of bromocyclopropanes with nitrogen ylides generated in situ from N-benzyl carboxamides. It is shown that this reaction involves cyclopropene intermediates and allows for the facile and expeditious preparation of 3-azabicyclo[3.1.0]hexan-2-one scaffolds.
Asunto(s)
Amidas/química , Compuestos de Bencilo/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Ciclopropanos/química , Hexanos/síntesis química , Aniones/química , Ciclización , Ciclopropanos/síntesis química , HalogenaciónRESUMEN
Polymer-based paclitaxel (PTX) conjugates have demonstrated application potentials to improve the water solubility and enhance the efficiency of drug delivery. In this study, a novel HA-based drug conjugate, HA-6-PTX, was designed and successfully synthesized by chemically grafting PTX to the C-6 position of N-acetyl-d-glucosamine (GlcNAc) of hyaluronic acid (HA) using hexanediamine as the linker. Leaving the carboxylate of HA chain unaffected, the conjugate with drug loading as high as 21.8% showed an excellent water solubility of 168mg/mL and exhibited increased drug release in the presence of hyaluronidase. Compared to free PTX, HA-6-PTX demonstrated increased cytotoxicity and enhanced apoptosis-inducing effect against HepG2 and A549 cells due to the increased cellular uptake of drug via HA-receptor mediated endocytosis. It was concluded that the HA-6-PTX conjugate could be potentially utilized for further exploration as targeted drug delivery to enhance antitumor efficacy.
Asunto(s)
Acetamidas/química , Diaminas/química , Sistemas de Liberación de Medicamentos , Hexanos/química , Ácido Hialurónico/química , Neoplasias/tratamiento farmacológico , Paclitaxel/química , Paclitaxel/uso terapéutico , Acetamidas/síntesis química , Apoptosis/efectos de los fármacos , Espectroscopía de Resonancia Magnética con Carbono-13 , Muerte Celular/efectos de los fármacos , Diaminas/síntesis química , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Citometría de Flujo , Células Hep G2 , Hexanos/síntesis química , Humanos , Ácido Hialurónico/síntesis química , Neoplasias/patología , Paclitaxel/farmacología , Espectroscopía de Protones por Resonancia MagnéticaRESUMEN
An improved synthesis of rings DEF of solanoeclepin A has been achieved from ent-Hajos Parrish ketone. A key tricyclo[5.3.2.01,6]decene intermediate having an additional vinyl group as a precursor of a hydroxyl functionality was synthesized, in which the key steps included (i) a [2,3]-Wittig rearrangement to provide trans-hydroindene with C11(R)-configuration, (ii) the introduction of a vinyl group as a masked OH at C6, (iii) an oxymercurative aldol to synthesize the tricyclo[5.3.2.01,6]decene moiety, (iv) an oxidative C-C bond cleavage to yield an aldehyde and an unsaturated methyl ketone, and (v) a radical cyclization for the cyclobutane ring formation to provide the tricyclo[5.2.1.01,6]decene compound.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Hexanos/síntesis química , Hidrocarburos Aromáticos con Puentes/química , Ciclización , Hexanos/química , Conformación MolecularRESUMEN
A palladium-catalyzed cyclopropanation of internal alkenes with N-tosylhydrazones is presented. This gram-scale cyclopropanation reaction of maleimides provides a wide spectrum of 3-azabicyclo[3.1.0]hexane derivatives in high yields and diastereoselectivities. The major diastereoisomers could be easily isolated by chromatography on silica gel. This protocol provides a practical route to the mu opioid receptor antagonist CP-866,087.
Asunto(s)
Compuestos de Azabiciclo/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Ciclopropanos/síntesis química , Hexanos/síntesis química , Hidrazonas/química , Maleimidas/química , Paladio/química , Compuestos de Tosilo/química , Compuestos de Azabiciclo/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Catálisis , Ciclopropanos/química , Hexanos/química , Estructura MolecularRESUMEN
An enantioselective synthesis of an intermediate in the Tanino total synthesis of solanoeclepin A has been developed. The key step was an intramolecular [2+2] photocycloaddition, which led to the tricyclo[5.2.1.0(1, 6)] decane core in six steps. The first photosubstrate, prepared through an indium-mediated Barbier-type reaction, gave an excellent [2+2] cycloaddition, but it could not be obtained in sufficient enantiopurity. The second photosubstrate, prepared through an asymmetric allene diborylation in high enantiomeric excess, gave the [2+2] cycloaddition product in high yield on irradiation at 365â nm on 20â g scale in a flow system. Other important steps were the replacement of a boronate group at the quaternary carbon by a vinyl group and diastereoselective cyclopropanation of an allylic alcohol.
Asunto(s)
Alcadienos/química , Hidrocarburos Aromáticos con Puentes/síntesis química , Hexanos/síntesis química , Compuestos Policíclicos/síntesis química , Hidrocarburos Aromáticos con Puentes/química , Reacción de Cicloadición , Hexanos/química , Compuestos Policíclicos/química , EstereoisomerismoRESUMEN
A stereocontrolled synthesis of the ABC rings of solanoeclepin A has been achieved. The seven-membered ring B was synthesized by an intramolecular Prins-ene reaction between an aldehyde and an enyne-dicobalthexacarbonyl complex. The acetylene in this synthesis plays multiple roles: to join the A and C rings, to allow stereoselective cyclization via dicobalthexacarbonyl complexation, and to facilitate Nicholas cation stabilization followed by deprotonation to form an endo-cyclic olefin (Nicholas-Prins cyclization).
Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Hexanos/síntesis química , Aldehídos/química , Hidrocarburos Aromáticos con Puentes/química , Ciclización , Hexanos/química , Estructura Molecular , EstereoisomerismoRESUMEN
The highly strained tricyclo[5.2.1.0(1,6)]decene skeleton of solanoeclepin A was synthesized through two key C-C bond forming processes; thus, a Hg(TFA)2-mediated oxymercuration followed an intramolecular aldol reaction to B and a SmI2-mediated cyclization of C between an aldehyde and an unsaturated ester to form the cyclobutane D having a tricyclo[5.2.1.0(1,6)]dodecene.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Hexanos/síntesis química , Aldehídos/química , Hidrocarburos Aromáticos con Puentes/química , Ciclización , Ciclobutanos/química , Hexanos/química , Estructura Molecular , EstereoisomerismoRESUMEN
The acid-catalysed thermal rearrangements of a family of N-aryl 2-azabicyclo[3.1.0]hexanes is described. These substrates, designed in such a way that the aromatic system is conjugated with an alkene group located at the ortho position relative to the nitrogen atom, have been prepared by using an intramolecular Kulinkovich-deâ Meijere reaction. The rearrangements can then be conducted either under standard thermal conditions or with microwave activation. Depending on the conditions applied and the substitution pattern, dihydroquinoline or polycyclic aminocyclobutane derivatives can be obtained. A mechanistic discussion is provided, with the proposition of the initial protonation of the aminocyclopropane moiety to give an iminium intermediate. By analogy with related intermolecular reactions, the involvement of electrocyclic reactions among the series of elementary steps that follow is put forward.
Asunto(s)
Ciclobutanos/química , Hexanos/síntesis química , Catálisis , Hexanos/química , Simulación de Dinámica Molecular , Estereoisomerismo , TitanioRESUMEN
In light of diminishing petroleum feedstocks, there is significant interest in developing carbohydrate defunctionalization reactions. In this context we have examined the use of iridium pincer catalysts for the hydrosilylative reduction of sugars, and we report herein complete reduction of silyl-protected glucose to a mixture of hexane isomers.
Asunto(s)
Glucosa/química , Hexanos/síntesis química , Iridio/química , Silanos/química , Catálisis , Hexanos/química , Estructura MolecularRESUMEN
(N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)-enhancing modifications, i.e., 2-(arylethynyl)adenine and N(6)-methyl or N(6)-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K(i) â¼0.6 nM, N(6)-methyl 2-(halophenylethynyl) analogues 13 and 14). Combined 2-arylethynyl-N(6)-3-chlorobenzyl substitutions preserved A(3)AR affinity/selectivity in the (N)-methanocarba series (e.g., 3,4-difluoro full agonist MRS5698 31, K(i) 3 nM, human and mouse A(3)) better than that for ribosides. Polyaromatic 2-ethynyl N(6)-3-chlorobenzyl analogues, such as potent linearly extended 2-p-biphenylethynyl MRS5679 34 (K(i) hA(3) 3.1 nM; A(1), A(2A), inactive) and fluorescent 1-pyrene adduct MRS5704 35 (K(i) hA(3) 68.3 nM), were conformationally rigid; receptor docking identified a large, mainly hydrophobic binding region. The vicinity of receptor-bound C2 groups was probed by homology modeling based on recent X-ray structure of an agonist-bound A(2A)AR, with a predicted helical rearrangement requiring an agonist-specific outward displacement of TM2 resembling opsin. Thus, the X-ray structure of related A(2A)AR is useful in guiding the design of new A(3)AR agonists.
Asunto(s)
Agonistas del Receptor de Adenosina A3/síntesis química , Adenosina/análogos & derivados , Adenosina/síntesis química , Alquinos/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Hexanos/síntesis química , Receptor de Adenosina A3/metabolismo , Adenosina/química , Adenosina/farmacología , Agonistas del Receptor de Adenosina A3/química , Agonistas del Receptor de Adenosina A3/farmacología , Alquinos/química , Alquinos/farmacología , Animales , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacología , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X , Diseño de Fármacos , Células HEK293 , Hexanos/química , Hexanos/farmacología , Humanos , Ratones , Modelos Moleculares , Conformación Molecular , Conformación Proteica , Ensayo de Unión Radioligante , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
3-Azabicyclo[3.1.0]hexane compounds were designed as novel achiral µ opioid receptor ligands for the treatment of pruritus in dogs. In this paper, we describe the SAR of this class of opioid ligand, highlighting changes to the lead structure which led to compounds having picomolar binding affinity, selective for the µ receptor over δ and κ subtypes. Some subtleties of functional activity will also be described.
Asunto(s)
Antipruriginosos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Hexanos/síntesis química , Prurito/tratamiento farmacológico , Receptores Opioides mu/antagonistas & inhibidores , Animales , Antipruriginosos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Perros , Cobayas , Hexanos/farmacología , Humanos , Técnicas In Vitro , Cinética , Ligandos , Prurito/metabolismo , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Relación Estructura-ActividadRESUMEN
Cyst nematodes are troublesome parasites that live on, and destroy, a range of important host vegetable plants. Damage caused by the potato cyst nematode has now been reported in over 50 countries. One approach to eliminating the problem is to stimulate early hatching of the nematodes, but key hatching stimuli are not naturally available in sufficient quantities to do so. Here, we report the first chemical synthesis of solanoeclepin A, the key hatch-stimulating substance for potato cyst nematode. The crucial steps in our synthesis are an intramolecular cyclization reaction for construction of the highly strained tricyclo[5.2.1.0¹'6]decane skeleton (DEF ring system) and an intramolecular Diels-Alder reaction of a furan derivative for the synthesis of the ABC carbon framework. The present synthesis has the potential to contribute to addressing one of the critical food issues of the twenty-first century.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Hexanos/síntesis química , Nematodos/efectos de los fármacos , Animales , Hidrocarburos Aromáticos con Puentes/farmacología , Hexanos/farmacología , Nematodos/fisiología , Control de Plagas/métodosRESUMEN
Herein we report a detailed description of the structure-activity relationships for a novel series of "C-linked" 1,2,4-triazolylazabicyclo[3.1.0]hexanes. These derivatives are endowed with very high in vitro affinity and selectivity for the dopamine D(3) receptor. An optimization with respect to undesired affinity toward the hERG potassium channel is also reported. Members of this compound series also show excellent in vitro and in vivo pharmacokinetic properties.
Asunto(s)
Compuestos Aza/química , Compuestos Bicíclicos con Puentes/química , Hexanos/química , Receptores de Dopamina D3/antagonistas & inhibidores , Triazoles/química , Animales , Sitios de Unión , Simulación por Computador , Hexanos/síntesis química , Hexanos/farmacocinética , Humanos , Ratas , Receptores de Dopamina D3/metabolismo , Relación Estructura-ActividadAsunto(s)
Alquenos/química , Bismuto/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Ciclopropanos/química , Hexanos/química , Compuestos de Sulfhidrilo/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Catálisis , Cristalografía por Rayos X , Hexanos/síntesis química , Metano/análogos & derivados , Metano/química , Conformación Molecular , EstereoisomerismoRESUMEN
The mild and efficient PtCl(2)-catalyzed cycloisomerization of 1,6-enynes containing a heteroatom substituent at the propargylic position is described. The reactions led to the formation of 1-alkenylbicyclo[3.1.0]hexanes in good to excellent yields or 2-(bicyclo[3.1.0]hex-1-yl)acetaldehydes in moderate yields.
Asunto(s)
Alquinos/química , Compuestos Bicíclicos con Puentes/síntesis química , Hexanos/síntesis química , Compuestos de Platino/química , Acetaldehído/química , Alquenos/química , Compuestos Bicíclicos con Puentes/química , Catálisis , Ciclización , Hexanos/química , Isomerismo , Espectroscopía de Resonancia Magnética , Solventes/química , TemperaturaRESUMEN
The effective formation of 1-azabicyclo[3.1.0]hexane (5) by treatment of 2-(bromomethyl)pyrrolidine hydrobromide (4) with n-BuLi was established, with the reaction occurring by a rational reaction pathway via the open chain transition state 8 based on intermolecular Br...Li(+) coordination (SN2 process). The reaction of 5 with electrophiles 13a-n gave the corresponding pyrrolidines 14a-n and piperidine 6, 15a-g, i-n. The selectivity of the products in this reaction appeared to be controlled by equilibrium.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Hexanos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Cristalografía por Rayos X , Hexanos/química , Conformación Molecular , Compuestos Organometálicos/química , Pirrolidinas/químicaRESUMEN
Three unique diastereoisomers of 2,3,4,5-tetrafluorohexane have been prepared, compounds intermediate between hexane and perfluorohexane in their degree of fluorination, and they show very different conformational behaviour and physical properties.
Asunto(s)
Compuestos de Flúor/síntesis química , Hexanos/síntesis química , Naftalenos/síntesis química , Cristalografía por Rayos X , Compuestos de Flúor/química , Hexanos/química , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Naftalenos/química , Fotoquímica , Piranos/química , Estereoisomerismo , Sulfonas/química , Rayos UltravioletaAsunto(s)
Hexanos/síntesis química , Paladio/química , Catálisis , Ciclización , Hexanos/química , Oxidación-ReducciónRESUMEN
Novel 5-X-substituted-2-azabicyclo[2.1.1]hexanes (X = 5-syn-Cl, -Br, -I, -Ph, -NHCOOR (R = Me, Bn, t-Bu), -CH2CH2COOMe and X = 5-anti-Br, -I, -Ph) were synthesized from the X = 5-syn-carboxy derivative. New 5-anti-X-2-azabicyclo[2.1.1]hexanes, X = NHCOOR (R = Me, Bn), were prepared stereoselectively from the X = 5-anti-carboxy substrate.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Hexanos/química , Pirrolidinas/síntesis química , Ácidos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Ésteres , Hexanos/síntesis química , Yoduros/química , Oxidantes/química , EstereoisomerismoRESUMEN
[reaction: see text] A general synthetic strategy for the preparation of functionalized bicyclo[3.1.0]hexanes is described. The new approach employs a cross metathesis step designed to functionalize the appropriate terminal olefin of the bicyclo[3.1.0]hexane precursor and a carbene-mediated intramolecular cyclopropanation reaction on the corresponding diazo intermediate. This combined methodology allowed the diastereoselective introduction of chemically diverse substituents at the tip of the cyclopropane group, except in cases where the substituents consisted of electron-withdrawing groups where a competing [3 + 2] cycloaddition predominated.