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1.
Org Biomol Chem ; 16(2): 285-294, 2018 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-29242861

RESUMO

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.


Assuntos
Amidas/química , Compostos de Benzil/química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Ciclopropanos/química , Hexanos/síntese química , Ânions/química , Ciclização , Ciclopropanos/síntese química , Halogenação
2.
Carbohydr Polym ; 181: 150-158, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29253957

RESUMO

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.


Assuntos
Acetamidas/química , Diaminas/química , Sistemas de Liberação de Medicamentos , Hexanos/química , Ácido Hialurônico/química , Neoplasias/tratamento farmacológico , Paclitaxel/química , Paclitaxel/uso terapêutico , Acetamidas/síntese química , Apoptose/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Morte Celular/efeitos dos fármacos , Diaminas/síntese química , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Citometria de Fluxo , Células Hep G2 , Hexanos/síntese química , Humanos , Ácido Hialurônico/síntese química , Neoplasias/patologia , Paclitaxel/farmacologia , Espectroscopia de Prótons por Ressonância Magnética
3.
Org Biomol Chem ; 15(5): 1228-1235, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28094400

RESUMO

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.


Assuntos
Compostos Azabicíclicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Ciclopropanos/síntese química , Hexanos/síntese química , Hidrazonas/química , Maleimidas/química , Paládio/química , Compostos de Tosil/química , Compostos Azabicíclicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Catálise , Ciclopropanos/química , Hexanos/química , Estrutura Molecular
4.
J Org Chem ; 82(4): 2045-2058, 2017 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-28117589

RESUMO

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.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Hexanos/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Ciclização , Hexanos/química , Conformação Molecular
5.
Chemistry ; 22(4): 1266-9, 2016 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-26646583

RESUMO

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 365 nm on 20 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.


Assuntos
Alcadienos/química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hexanos/síntese química , Compostos Policíclicos/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Reação de Cicloadição , Hexanos/química , Compostos Policíclicos/química , Estereoisomerismo
6.
Org Lett ; 16(22): 5948-51, 2014 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-25376022

RESUMO

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).


Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Hexanos/síntese química , Aldeídos/química , Hidrocarbonetos Aromáticos com Pontes/química , Ciclização , Hexanos/química , Estrutura Molecular , Estereoisomerismo
7.
Org Lett ; 16(16): 4166-9, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25058474

RESUMO

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.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Hexanos/síntese química , Aldeídos/química , Hidrocarbonetos Aromáticos com Pontes/química , Ciclização , Ciclobutanos/química , Hexanos/química , Estrutura Molecular , Estereoisomerismo
8.
Chemistry ; 19(35): 11759-67, 2013 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-23852657

RESUMO

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-de 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.


Assuntos
Ciclobutanos/química , Hexanos/síntese química , Catálise , Hexanos/química , Simulação de Dinâmica Molecular , Estereoisomerismo , Titânio
9.
J Am Chem Soc ; 135(4): 1225-7, 2013 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-23305415

RESUMO

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.


Assuntos
Glucose/química , Hexanos/síntese química , Irídio/química , Silanos/química , Catálise , Hexanos/química , Estrutura Molecular
10.
J Med Chem ; 55(10): 4847-60, 2012 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-22559880

RESUMO

(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) ∼0.6 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.


Assuntos
Agonistas do Receptor A3 de Adenosina/síntese química , Adenosina/análogos & derivados , Adenosina/síntese química , Alcinos/síntese química , Compostos Bicíclicos com Pontes/síntese química , Hexanos/síntese química , Receptor A3 de Adenosina/metabolismo , Adenosina/química , Adenosina/farmacologia , Agonistas do Receptor A3 de Adenosina/química , Agonistas do Receptor A3 de Adenosina/farmacologia , Alcinos/química , Alcinos/farmacologia , Animais , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Células CHO , Cricetinae , Cricetulus , Cristalografia por Raios X , Desenho de Fármacos , Células HEK293 , Hexanos/química , Hexanos/farmacologia , Humanos , Camundongos , Modelos Moleculares , Conformação Molecular , Conformação Proteica , Ensaio Radioligante , Estereoisomerismo , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 22(6): 2200-3, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22357342

RESUMO

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.


Assuntos
Antipruriginosos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Hexanos/síntese química , Prurido/tratamento farmacológico , Receptores Opioides mu/antagonistas & inibidores , Animais , Antipruriginosos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cães , Cobaias , Hexanos/farmacologia , Humanos , Técnicas In Vitro , Cinética , Ligantes , Prurido/metabolismo , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade
12.
Nat Chem ; 3(6): 484-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21602865

RESUMO

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.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Hexanos/síntese química , Nematoides/efeitos dos fármacos , Animais , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hexanos/farmacologia , Nematoides/fisiologia , Controle de Pragas/métodos
13.
ChemMedChem ; 5(5): 705-15, 2010 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-20232439

RESUMO

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.


Assuntos
Compostos Aza/química , Compostos Bicíclicos com Pontes/química , Hexanos/química , Receptores de Dopamina D3/antagonistas & inibidores , Triazóis/química , Animais , Sítios de Ligação , Simulação por Computador , Hexanos/síntese química , Hexanos/farmacocinética , Humanos , Ratos , Receptores de Dopamina D3/metabolismo , Relação Estrutura-Atividade
14.
J Org Chem ; 74(24): 9550-3, 2009 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-19925017

RESUMO

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.


Assuntos
Alcinos/química , Compostos Bicíclicos com Pontes/síntese química , Hexanos/síntese química , Compostos de Platina/química , Acetaldeído/química , Alcenos/química , Compostos Bicíclicos com Pontes/química , Catálise , Ciclização , Hexanos/química , Isomerismo , Espectroscopia de Ressonância Magnética , Solventes/química , Temperatura
16.
Chem Pharm Bull (Tokyo) ; 57(10): 1142-6, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19801877

RESUMO

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.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Hexanos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Cristalografia por Raios X , Hexanos/química , Conformação Molecular , Compostos Organometálicos/química , Pirrolidinas/química
17.
Org Biomol Chem ; 6(17): 3105-8, 2008 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-18698469

RESUMO

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.


Assuntos
Compostos de Flúor/síntese química , Hexanos/síntese química , Naftalenos/síntese química , Cristalografia por Raios X , Compostos de Flúor/química , Hexanos/química , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Naftalenos/química , Fotoquímica , Piranos/química , Estereoisomerismo , Sulfonas/química , Raios Ultravioleta
19.
J Org Chem ; 71(5): 2090-8, 2006 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-16496997

RESUMO

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.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Hexanos/química , Pirrolidinas/síntese química , Ácidos/química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Ésteres , Hexanos/síntese química , Iodetos/química , Oxidantes/química , Estereoisomerismo
20.
Org Lett ; 8(4): 705-8, 2006 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-16468747

RESUMO

[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.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Ciclopropanos/química , Hexanos/síntese química , Nucleosídeos/síntese química , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Ciclização , Hexanos/química , Conformação Molecular , Estrutura Molecular , Nucleosídeos/química
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