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1.
Chem Commun (Camb) ; 57(80): 10355-10358, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34533145

RESUMO

Herein we report for the first time that the thiosugar moiety can be used both as a directing group enabling the regioselective activation of a C-H bond of biaryl scaffolds and as a chiral source inducing axial chirality. Our approach enables the easy generation of complex thioglycoside atropoisomers, thus paving the way to new products of potential biological interest.


Assuntos
Compostos de Bifenilo/síntese química , Tioglicosídeos/síntese química , Alcenos/síntese química , Catálise , Paládio/química , Estereoisomerismo
2.
J Exp Clin Cancer Res ; 40(1): 33, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33461580

RESUMO

BACKGROUND: Despite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent®), or by combinations of anti-angiogenic drugs with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable. Hence, new relevant treatments are urgently needed. The VEGFs coreceptors, Neuropilins 1, 2 (NRP1, 2) are expressed on several tumor cells including ccRCC. We analyzed the role of the VEGFs/NRPs signaling in ccRCC aggressiveness and evaluated the relevance to target this pathway. METHODS: We correlated the NRP1, 2 levels to patients' survival using online available data base. Human and mouse ccRCC cells were knocked-out for the NRP1 and NRP2 genes by a CRISPR/Cas9 method. The number of metabolically active cells was evaluated by XTT assays. Migration ability was determined by wound closure experiments and invasion ability by using Boyden chamber coated with collagen. Production of VEGFA and VEGFC was evaluated by ELISA. Experimental ccRCC were generated in immuno-competent/deficient mice. The effects of a competitive inhibitor of NRP1, 2, NRPa-308, was tested in vitro and in vivo with the above-mentioned tests and on experimental ccRCC. NRPa-308 docking was performed on both NRPs. RESULTS: Knock-out of the NRP1 and NRP2 genes inhibited cell metabolism and migration and stimulated the expression of VEGFA or VEGFC, respectively. NRPa-308 presented a higher affinity for NRP2 than for NRP1. It decreased cell metabolism and migration/invasion more efficiently than sunitinib and the commercially available NRP inhibitor EG00229. NRPa-308 presented a robust inhibition of experimental ccRCC growth in immunocompetent and immunodeficient mice. Such inhibition was associated with decreased expression of several pro-tumoral factors. Analysis of the TCGA database showed that the NRP2 pathway, more than the NRP1 pathway correlates with tumor aggressiveness only in metastatic patients. CONCLUSIONS: Our study strongly suggests that inhibiting NRPs is a relevant treatment for mccRCC patients in therapeutic impasses and NRPa-308 represents a relevant hit.


Assuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Animais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Técnicas de Inativação de Genes , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Camundongos , Modelos Moleculares , Metástase Neoplásica , Neuropilina-1/antagonistas & inibidores , Neuropilina-1/genética , Neuropilina-2/antagonistas & inibidores , Neuropilina-2/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Org Biomol Chem ; 19(5): 1037-1046, 2021 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-33395455

RESUMO

An efficient silver-catalyzed tandem reaction for the formation of 1,2-dihydroisoquinoline derivatives is herein reported. Highly functionalized multiheterocyclic scaffolds are accessible in a straightforward manner using readily accessible starting materials under mild conditions. This methodology offers an attractive route for the synthesis and development of a biologically relevant new heterocyclic pharmacophore, merging the biological activities of isoquinolines with those of various nitrogen-containing heterocycles (indoles, pyrroles) incorporated during the tandem reaction. Mechanistic investigations were also conducted along with a large scope and limitation study, modifying various sites of this pharmacophore.


Assuntos
Isoquinolinas/química , Prata/química , Catálise , Isomerismo , Isoquinolinas/síntese química , Cinética , Temperatura
4.
J Org Chem ; 86(5): 3758-3767, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33439649

RESUMO

Rearrangement reactions in organic chemistry are attractive strategies to build efficiently complex scaffolds, in just one step, from simple starting materials. Among them, aryl migrations are certainly one of the most useful and straightforward rearrangement for building attractive carbon-carbon bonds. Of note, anionic aryl migration reactions have been largely described compared to their radical counterparts. Recently, visible-light catalysis has proven its efficiency to generate such radical rearrangements due to the concomitant loss of a particle (often CO2 or SO2), which is the driving-force of the reaction. Here, we disclose a Smiles-type rearrangement, triggered by a phosphorus-containing unit (arylphosphoramidate), therefore called "phospho-Smiles" rearrangement, allowing a Csp2-Csp2 bond formation thanks to a 1,4-aryl migration reaction. In addition, combining this approach with a radical hydroamination/amination reaction produces an amination/phospho-Smiles cascade particularly attractive, for instance, to investigate the synthesis of the phthalazine core, a scarcely described scaffold of interest for medicinal chemistry projects.


Assuntos
Química Orgânica , Luz , Aminação , Carbono , Catálise
5.
Chemistry ; 27(11): 3581-3607, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32996634

RESUMO

Rearrangement reactions are certainly one of the most useful approaches towards complex structures in organic chemistry. With efficient conditions, it is indeed possible to convert simple substrates into highly functionalized products. Moreover, combining this approach with an attractive initiation process, such as visible-light catalysis, makes these reactions particularly powerful. Recently, tremendous improvements have been made, owing to a better understanding of photoredox mechanisms. In this review, recent progress on visible-light aryl migration reactions is discussed, focusing especially on Smiles rearrangement and related reactions.

6.
Bioorg Med Chem Lett ; 29(24): 126710, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31699610

RESUMO

We report herein the synthesis of a newly described anti-cancer agent, NRPa-308. This compound antagonizes Neuropilin-1, a multi-partners transmembrane receptor overexpressed in numerous tumors, and thereby validated as promising target in oncology. The preparation of NRPa-308 proved challenging because of the orthogonality of the amide and sulphonamide bonds formation. Nevertheless, we succeeded a gram scale synthesis, according to an expeditious three steps route, without intermediate purification. This latter point is of utmost interest in reducing the ecologic impact and production costs in the perspective of further scale-up processes. The purity of NRPa-308 has been attested by means of conventional structural analyses and its crystallisation allowed a structural assessment by X-Ray diffraction. We also reported the remarkable chemical stability of this molecule in acidic, neutral and basic aqueous media. Eventually, we observed for the first time the accumulation of NRPa-308 in two types of human breast cancer cells MDA-MB231 and BT549.


Assuntos
Antineoplásicos/uso terapêutico , Neuropilina-1/uso terapêutico , Antineoplásicos/farmacologia , Humanos , Estrutura Molecular
7.
J Org Chem ; 84(10): 6278-6285, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-30990317

RESUMO

Visible light catalysis allows the regioselective synthesis of oxazolines in high yields. The mild photosensitized manifold leverages the intermolecular formation of oxazolines with a wide functional group tolerance on both benzoyl azides and alkenes partners. Mechanistic investigations suggest the sensitization of the azide moiety as the key activation step.

8.
Org Lett ; 18(19): 4814-4817, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27618124

RESUMO

A silver-catalyzed cycloisomerization reaction of a series of o-alkynylbenzohydroxamic acids is reported. Several 5-exo-dig and 6-endo-dig modes of cyclization were observed with the nitrogen or oxygen atoms of the amide group acting as nucleophiles. The selectivity was strongly dependent on the silver salt used and on the presence of triphenylphosphine as an additive. Indeed, while the use of Ag2O at room temperature allowed the isolation of isobenzofuran-1-one oximes (7 compounds, 48-92% yield), [Ag(Im)]n with the concomitant addition of 2 equiv of PPh3 led to a switch in selectivity and to a family of isoindolin-1-ones (10 compounds, 59-87%).

9.
Chem Sci ; 7(8): 5002-5006, 2016 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30155150

RESUMO

We report the synthesis of various phthalazines via a new cascade reaction, initiated by visible light photocatalysis, involving a radical hydroamination reaction followed by a radical Smiles rearrangement. Phthalazine derivatives are obtained in high yields and from a broad scope readily accessible ortho-alkynylsulfonohydrazone precursors. The mild photoredox conditions ensure an excellent functional group tolerance. Application of this strategy to a one-pot protocol starting from the corresponding carbonyl compounds, and subsequent functionalization allow the rapid synthesis of structurally diverse structures.

10.
J Org Chem ; 80(15): 7519-29, 2015 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-26176588

RESUMO

A mild and general method for the direct alkynylation of azoles such as pyrrole, indole, and 7-azaindole is described here. Using a simple catalytic system such as Pd(OAc)2 (2.5 mol %), P(tBu)2Me·HBF4 (5 mol %), and NaOAc (2 equiv) allowed the regioselective introduction of various alkynyl residues at the C-2 position of pyrroles. Interestingly, C-2 alkynylation was also observed on C-3-substituted indoles, whereas classical C-3 alkynylation was obtained on selected unsubstituted indoles and 7-azaindole. Our methodology has been illustrated by the efficient synthesis of a potential schizophrenia drug (dopamine D-4 inhibitor).

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.
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
13.
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
14.
Org Lett ; 12(18): 4042-5, 2010 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-20722380

RESUMO

PdCl(2)(MeCN)(2) in combination with dppp proved to be a powerful and efficient catalyst for the coupling of sterically hindered N-arylsulfonylhydrazones with aryl halides, thus providing a flexible and convergent access to tetrasubstituted olefins related to iso-combretastatin A4 in good yields. This new protocol has been applied successfully to the formal synthesis of biphenylisopropylidene 4-pyridine CYP17 inhibitor, 12b, of biological interest.


Assuntos
Alcenos/síntese química , Halogênios/química , Hidrazonas/química , Paládio/química , Estilbenos/química , Alcenos/farmacologia , Catálise , Estrutura Molecular , Estereoisomerismo , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Estilbenos/farmacologia , Tubulina (Proteína)/química
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