Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 68
Filtrar
1.
Epilepsia ; 63(11): 2911-2924, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36054371

RESUMO

OBJECTIVE: Many early-onset epilepsies present as developmental and epileptic encephalopathy associated with refractory seizures, altered psychomotor development, and disorganized interictal cortical activity. Abnormal upregulation of specific N-methyl-d-aspartate receptor (NMDA-R) subunits is being disentangled as one of the mechanisms of severe early-onset epilepsies. In tuberous sclerosis complex (TSC), upregulation of the GluN2C subunit of the NMDA-R with slow deactivation kinetic results in increased neuronal excitation and synchronization. METHODS: Starting from an available GluN2C/D antagonist, NMDA-R-modulating compounds were developed and screened using a patch clamp on neuronal culture to select those with the strongest inhibitory effect on glutamatergic NMDA currents. For these selected compounds, blood pharmacokinetics and passage through the blood-brain barrier were studied. We tested the effect of the most promising compounds on epileptic activity in Tsc1+/- mice brain slices with multielectrode array, and then in vivo at postnatal ages P14-P17, comparable with the usual age at epilepsy onset in human TSC. RESULTS: Using a double-electrode voltage clamp on isolated NMDA currents, we identified the most prominent antagonists of the GluN2C subunit with no effect on GluN2A as a means of preventing side effects. The best compound passing through the blood-brain barrier was selected. Applied in vivo in six Tsc1+/- mice at P14-P17, this compound reduced or completely stopped spontaneous seizures in four of them, and decreased the background activity disorganization. Furthermore, ictal-like discharges stopped on a human brain sample from an infant with epilepsy due to TSC. INTERPRETATION: Subunit-selective inhibition is a valuable target for developing drugs for severe epilepsies resulting from an upregulation of NMDA-R subunit-mediated transmission.


Assuntos
Epilepsia , Esclerose Tuberosa , Animais , Humanos , Lactente , Camundongos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Epilepsia/etiologia , Epilepsia/complicações , N-Metilaspartato , Receptores de N-Metil-D-Aspartato , Convulsões/etiologia , Convulsões/complicações , Esclerose Tuberosa/complicações
2.
Chemistry ; 22(42): 15006-15010, 2016 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-27557755

RESUMO

An efficient thioglycosylation of C(sp2 )-H bonds with thiosugars has been established for the first time. Using only Cu(OAc)2 ⋅H2 O as a catalyst and Ag2 CO3 as an additive in DMSO, the protocol proved to have broad scope, and a variety of complex thioglycosides have been prepared in good yields with exclusive ß-selectivity.

3.
Chemistry ; 22(32): 11365-70, 2016 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-27362372

RESUMO

The third generation of aminobiphenyl palladacycle pre-catalyst "G3-Xantphos" enables functionalization of peptides containing cysteine in high yields. The conjugation (bioconjugation) occurs chemoselectively at room temperature under biocompatible conditions. Extension of the method to protein functionalization allows selective bioconjugation of the trastuzumab antibody.


Assuntos
Cisteína/química , Paládio/química , Fosfinas/química , Proteínas/química , Xantenos/química , Catálise , Temperatura
4.
J Org Chem ; 81(2): 424-32, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26691351

RESUMO

An efficient Pd-catalyzed decarboxylative coupling of heterocyclic carboxylic acids with heterocyclic halides to achieve the synthesis of biheterocycles of biological interest has been reported. In all cases, the cross-coupling reactions take place rapidly in DMSO in good yields and efficiently proceed in the presence of a PdBr2/DPEphos catalytic system, furnishing the novel biheterocycles based on quinolin-4-one, quinolin-2-one, chromone, and coumarin scaffolds.

5.
Chemistry ; 21(23): 8375-9, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25876554

RESUMO

A general and efficient protocol for the palladium-catalyzed functionalization of mono- and polyglycosyl thiols by using the palladacycle precatalyst G3-XantPhos was developed. The C-S bond-forming reaction was achieved rapidly at room temperature with various functionalized (hetero)aryl-, alkenyl-, and alkynyl halides. The functional group tolerance on the electrophilic partner is typically high and anomer selectivities of thioglycosides are high in all cases studied. New sulfur nucleophiles such as thiophenols, alkythiols, and thioaminoacids (cysteine) were also successfully coupled to lead to the most general and practical method yet reported for the functionalization of thiols.

6.
J Org Chem ; 80(2): 751-61, 2015 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-25496127

RESUMO

An efficient Pd-catalyzed selective intramolecular arylation of functionalized N,N'-substituted 1-aminoindoles has been reported. In all cases, the reactions take place rapidly in DMA and efficiently proceed in the presence of a Pd(OAc)2/Dpephos catalytic system, furnishing the fused indolo[2,1-a]phthalazines in high yields. Additionally, the one-pot double C­H arylation at positions C-2 and C-3 of N,N'-substituted 1-aminoindoles is effective and leads to unknown complex scaffolds of biological interest.


Assuntos
Indóis/síntese química , Paládio/química , Catálise , Ciclização , Ligação de Hidrogênio , Indóis/química , Estrutura Molecular
7.
J Org Chem ; 80(13): 6715-27, 2015 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-26036279

RESUMO

A new three-component assembly reaction between N-tosylhydrazones, dihalogenated arenes, and boronic acids or boronate esters was developed, producing highly substituted 1,1-diarylethylenes in good yields. The two C-C bonds formed through this coupling have been catalyzed by a single Pd-catalyst in a one-pot fashion. It is noted that the one-pot pinacol boronate cross-coupling reaction generally provides products in high yields, offers an expansive substrate scope, and can address a broad range of aryl, styrene, vinyl, and heterocyclic olefinic targets. The scope of this one-pot coupling has been also extended to the synthesis of the 1,1-diarylethylene skeleton of the natural product ratanhine. The new compounds were evaluated for their cytotoxic activity, and this allowed the identification of compound 4ab that exhibits excellent antiproliferative activity in the nanomolar concentration range against HCT116 cancer cell lines.


Assuntos
Compostos de Boro/química , Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Etilenos/síntese química , Hidrazonas/química , Compostos de Vinila/síntese química , Compostos de Vinila/farmacologia , Catálise , Linhagem Celular , Ciclopropanos/química , Etilenos/química , Células HCT116/química , Células HCT116/efeitos dos fármacos , Humanos , Estrutura Molecular , Paládio/química , Compostos de Vinila/química
8.
Org Biomol Chem ; 13(44): 10904-16, 2015 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-26369372

RESUMO

An efficient synthesis of thioglycosylated benzo[e][1,4]oxathiepin-5-one and benzothiazepinone derivatives by a sequence of palladium-catalyzed glycosyl thiol arylation followed by deprotection-lactonization reactions has been reported. This diversity-oriented strategy enabled access to unknown complex cyclic scaffolds with polyhydroxylated appendages of biological interest.


Assuntos
Benzotiepinas/química , Lactonas/química , Paládio/química , Compostos de Sulfidrila/química , Tiazepinas/química , Catálise , Glicosilação
9.
J Org Chem ; 79(16): 7583-92, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25029590

RESUMO

The synthesis of amino-substituted N-vinylazoles was achieved by a new palladium-assisted tandem catalytic reaction involving N-tosylhydrazones, halo-substituted azoles, and amines. Accordingly, two Csp(2)-N bonds were formed through two mechanistically distinct reactions using a single Pd(II)/Pd(0) catalyst system in a one-pot fashion. This work paves the way for the design of biological relevant compounds in an amino-substituted N-vinylindole series. Among several polyoxygenated derivatives evaluated, compounds 5e and 5u were found to exhibit good antiproliferative activity.


Assuntos
Aminas/química , Proliferação de Células/efeitos dos fármacos , Hidrazonas/química , Indóis/química , Paládio/química , Compostos de Tosil/síntese química , Compostos de Tosil/farmacologia , Compostos de Vinila/farmacologia , Catálise , Linhagem Celular Tumoral , Neoplasias do Colo , Humanos , Indóis/síntese química , Indóis/farmacologia , Estrutura Molecular , Compostos de Tosil/química , Compostos de Vinila/síntese química , Compostos de Vinila/química
10.
Org Biomol Chem ; 12(42): 8533-41, 2014 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-25237986

RESUMO

3-(Heteroaryl)quinolin-2(1H)-ones were synthesized in good to excellent yields using a bimetallic catalytic system through the C-H heteroarylation strategy. Starting from 3-bromoquinolin-2(1H)-ones, various azoles have been successfully used. In all cases, the reactions take place rapidly in dioxane and efficiently proceed in the presence of a bimetallic Pd(OAc)2/CuI as the catalyst, PPh3 as the ligand and LiOtBu or KOAc as the base.


Assuntos
Cobre/química , Paládio/química , Quinolonas/síntese química , Catálise , Halogenação , Quinolonas/química
11.
Chemistry ; 19(45): 15276-80, 2013 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-24108443

RESUMO

Unprotected thioglycosides were effective nucleophiles for Ni(0)-catalyzed C-S bond-forming reaction with functionalized (hetero)aryl, alkenyl, and alkynyl halides. The functional-group tolerance on the electrophilic partner was typically high and the anomeric selectivities of the thioglycosides were high in all cases. The efficiency of this general procedure was well-demonstrated by the synthesis of 4-methyl-7-thioumbelliferyl-ß-D-cellobioside (MUS-CB).


Assuntos
Níquel/química , Tioglicosídeos/química , Catálise , Temperatura
12.
J Org Chem ; 78(2): 445-54, 2013 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-23245545

RESUMO

The reactivity of sterically hindered N-tosylhydrazones 2 featuring ortho/ortho'-substituents on the aromatic ring with various ortho-, meta-, and para-substituted aryl halides 3 was investigated. To accomplish successfully this challenging coupling, fine-tuning of the reaction conditions were required. The newly established PdCl(2)(MeCN)(2)/Xphos/NaO-t-Bu/F-benzene system in a sealed tube is compatible with a broad spectrum of both coupling partners, regardless of their electronic and steric nature. This protocol has been applied successfully to the synthesis of a xanthene derivative.


Assuntos
Reagentes de Ligações Cruzadas/química , Etilenos/química , Etilenos/síntese química , Hidrazonas/química , Hidrazonas/síntese química , Hidrocarbonetos Halogenados/química , Hidrocarbonetos Halogenados/síntese química , Xantenos/síntese química , Catálise , Estrutura Molecular , Xantenos/química
13.
J Org Chem ; 78(17): 8485-95, 2013 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-23899168

RESUMO

In a fresh approach to the synthesis of N-vinylazoles, a ligand-free palladium catalytic system was found to promote the Csp(2)-N bond-forming reaction utilizing N-tosylhydrazones and N-H azoles. This process shows functional group tolerance; di-, tri-, and tetrasubstituted N-vinylazoles were obtained in high yields. Under the optimized conditions, the reaction proceeds with high stereoselectivity depending on the nature of the coupling partners.


Assuntos
Azóis/síntese química , Hidrazonas/química , Indóis/química , Paládio/química , Compostos de Tosil/química , Compostos de Vinila/síntese química , Azóis/química , Catálise , Ligantes , Estrutura Molecular , Oxirredução , Teoria Quântica , Compostos de Vinila/química
14.
Org Biomol Chem ; 11(23): 3808-16, 2013 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-23584212

RESUMO

An efficient and general palladium-catalyzed coupling of 3-chloro-quinoxalinones with a variety of nitrogen-containing nucleophiles such as (hetero)aromatic and aliphatic amides as well as some challenging weakly nucleophilic nitrogen compounds including lactams, carbamates and NH-containing azoles is described. In all cases, the reactions take place rapidly and cleanly in dioxane using Pd(OAc)2 as a catalyst, Xantphos as a ligand and K2CO3 as a base furnishing the coupling 3-N-substituted quinoxalinone products in good to excellent yields.


Assuntos
Nitrogênio/química , Paládio/química , Quinoxalinas/química , Catálise
15.
Org Biomol Chem ; 11(22): 3664-73, 2013 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-23615719

RESUMO

The synthesis of 2-α-styrylpyridines has been carried out by using the coupling of polyoxygenated N-tosylhydrazones with various 2-halopyridines. We demonstrated that the use of a catalytic amount of PdCl2(MeCN)2 in combination with a bidentate ferrocene DPPF or a monodentate alkyl phosphine (t)Bu2MeP-HBF4 constitutes an efficient protocol for this coupling, providing 2-α-styrylpyridines 2 in satisfactory to good yields. Among several polyoxygenated derivatives 2 evaluated, compound 2aa was found to exhibit excellent antiproliferative and antimitotic activities comparable to that of the reference compound isoCA-4.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Hidrazonas/química , Piridinas/síntese química , Piridinas/farmacologia , Estirenos/síntese química , Estirenos/farmacologia , Antineoplásicos/química , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colo/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Halogenação , Humanos , Hidrazonas/síntese química , Paládio/química , Piridinas/química , Estirenos/química
16.
Org Biomol Chem ; 11(3): 430-42, 2013 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-23047722

RESUMO

The synthesis and structure-activity relationships associated with a series of 1,1-diarylethylene tubulin polymerization inhibitors 3 and 4 are described. The key step for their preparation involves a palladium-catalyzed coupling of N-arylsulfonylhydrazones with aryl halides, thus providing flexible and convergent access to tri- and tetrasubstituted 1,1-diarylolefins 3 and 4 related to isocombretastatin A-4 (isoCA-4). These compounds have been evaluated for tubulin polymerization inhibitory activity as well as for cytotoxic activity. The most potent compounds are 1,1-diaryl-2-methoxyethylenes 4b, 4d and 4e having a trisubstituted double bond. They exhibited good antiproliferative activity against various human cancer cell lines (GI(50) = 8-80 nM). Compounds 4b and 4e strongly inhibited tubulin polymerization with IC(50) values of 2 and 3 µM, respectively, and induced cell cycle arrest in the G(2)/M phase in the K562 cell line. Docking studies in the colchicine binding site of tubulin allowed identification of residues most likely to interact with these inhibitors and explain their potent anti-tubulin activity.


Assuntos
Alcenos/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Estilbenos/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química
17.
J Org Chem ; 76(12): 4995-5005, 2011 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-21524121

RESUMO

3-(N-Substituted) 4(1H)-quinolinones were synthesized using the copper-catalyzed Ullmann C-N bond forming strategy in moderate to quantitative yields. Starting from 3-halo-4(1H)-quinolones, various nucleophiles including amides, lactams, sulfonamides and NH-containing azoles have been used successfully. In all cases, the reactions take place rapidly in toluene and proceed by using copper powder as a catalyst, DMEDA as a ligand and K(2)CO(3) as a base. In addition, other related heterocycles such as 3-bromoquinolin-2(1H)-ones, 3-bromocoumarin, and 3,5-dibromo-2-pyridone show good to very high reactivity with various nucleophiles under our Cu/DMEDA catalyst system.


Assuntos
Cobre/química , Compostos de Nitrogênio/química , Quinolonas/química , Aminação , Catálise , Estrutura Molecular , Paládio/química
18.
Org Biomol Chem ; 9(18): 6200-4, 2011 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-21796313

RESUMO

A general procedure for the reductive coupling of N-tosylhydrazones with amines in the presence of Cu(acac)(2) and Cs(2)CO(3) has been developed. The protocol is very effective and chemoselective with various primary and secondary aliphatic amines, aminoalcohols as well as azole derivatives to give α-branched amines in good yields.


Assuntos
Aminas/química , Cobre/química , Hidrazonas/química , Aminas/síntese química , Catálise , Oxirredução
19.
Eur J Med Chem ; 199: 112355, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32402934

RESUMO

In this work, unique flavopiridol analogs bearing thiosugars, amino acids and heterocyclic moieties tethered to the flavopiridol via thioether and amine bonds mainly on its C ring have been prepared. The analogs bearing thioether-benzimidazoles as substituents have demonstrated high cytotoxic activity in vitro against up to seven cancer cell lines. Their cytotoxic effects are comparable to those of flavopiridol. The most active compound 13c resulting from a structure-activity relationship (SAR) study and in silico docking showed the best antiproliferative activity and was more efficient than the reference compound. In addition, compound 13c showed significant nanomolar inhibition against CDK9, CDK10, and GSK3ß protein kinases.


Assuntos
Antineoplásicos/farmacologia , Flavonoides/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Flavonoides/síntese química , Flavonoides/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
20.
Biochem Biophys Res Commun ; 379(2): 514-8, 2009 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-19118525

RESUMO

The cochaperone p23 is required for the chaperoning cycle of hsp90 and to enhance the maturation of several client proteins. Tosylcyclonovobiocic acids (4TCNA and 7TCNA) are potent analogs of novobiocin and induce cell cycle arrest, apoptosis and degradation of hsp90 client proteins in a panel of cancer cells. In this study, Western blotting shows that 4TCNA and 7TCNA triggered processing of the hsp90 cochaperone p23 in a dose-dependent manner. Small interfering RNA (siRNA)-mediated reduction of p23 expression in MCF-7 breast cancer cells did not block 4TCNA-induced caspase activation as assessed by the cleavage of PARP. This result indicates that 4TCNA-mediated cell death is a p23-independent process. In HT29 colon cancer cells, 4TCNA and 7TCNA up-regulated GRP78 and GRP94 supporting involvement of ER stress in apoptosis.


Assuntos
Proteínas de Choque Térmico HSP90/metabolismo , Oxirredutases Intramoleculares/efeitos dos fármacos , Neoplasias/enzimologia , Novobiocina/análogos & derivados , Novobiocina/farmacologia , Apoptose , Linhagem Celular Tumoral , Colágeno Tipo XI/metabolismo , Retículo Endoplasmático/metabolismo , Chaperona BiP do Retículo Endoplasmático , Receptor alfa de Estrogênio/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Glicoproteínas de Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Prostaglandina-E Sintases , Interferência de RNA , RNA Interferente Pequeno/genética , Estresse Fisiológico , Regulação para Cima
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA