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1.
Bioorg Med Chem ; 27(18): 4101-4109, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31371219

RESUMO

The design of conjugates displaying simultaneously high selectivity and high affinity for different subtypes of integrins is a current challenge. The arginine-glycine-aspartic acid amino acid sequence (RGD) is one of the most efficient short peptides targeting these receptors. We report herein the development of linear and cyclic fluoro-C-glycoside"RGD" conjugates, taking advantage of the robustness and hydrophilicity of C-glycosides. As attested by in vitro evaluation, the design of these C-glyco"RGD" with a flexible three-carbon triazolyl linker allows distinct profiles towards αIIbß3 and αvß3 integrins. Molecular-dynamics simulations confirm the suitability of cyclic C-glyco-c(RGDfC) to target αvß3 integrin. These C-glyco"RGD" could become promising biological tools in particular for Positron Emission Tomography imaging.

2.
Carbohydr Res ; 477: 1-10, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30927609

RESUMO

Functionalized carbohydrates and especially functionalized C-glycosides are useful intermediates for the synthesis of complex carbohydrates of interest. In this paper, we describe the synthesis of C-azidopropylglucopyranosides and give a full account of their regioselective acylation and alkylation. Alkylation of these C-glucosyl compounds containing 1,2-trans-diol, namely 2- and 3-OH were first optimized with benzyl bromide. The reaction has then been extended to various electrophiles thus providing 3-O-substituted C-glucosyl compounds. These results are one of the first examples of regioselective alkylation with functionalized electrophiles on glycosyl compounds featuring a trans-vicinal diol. Furthermore, we describe some results obtained during regioselective deprotection of 4,6-O-benzylidene protecting group. This work opens the way to the synthesis of complex carbohydrate derivatives.


Assuntos
Carboidratos/química , Glicosídeos/química , Alquilação , Configuração de Carboidratos , Estereoisomerismo
3.
Oncotarget ; 9(20): 15312-15325, 2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29632646

RESUMO

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the progress of new treatments, the risk of recurrence, morbidity, and death remains important. The neuropilin-1 (NRP-1) receptor has recently been implicated in tumor progression of MB, which seems to play an important role in the phenotype of cancer stem cells. Targeting this receptor appears as an interesting strategy to promote MB stem cells differentiation. Cancer stem-like cells of 3 MB cell lines (DAOY, D283-Med and D341-Med), classified in the more pejorative molecular subgroups, were obtained by in vitro enrichment. These models were characterized by an increase of NRP-1 and cancer stem cell markers (CD15, CD133 and Sox2), meanwhile a decrease of the differentiated cell marker Neurofilament-M (NF-M) was observed. Our previous work investigated potential innovative peptidomimetics that specifically target NRP-1 and showed that MR438 had a good affinity for NRP-1. This small molecule decreased the self-renewal capacity of MB stem cells for the 3 cell lines and reduced the invasive ability of DAOY and D283 stem cells while NRP-1 expression and cancer stem cell markers decreased at the same time. Possible molecular mechanisms were explored and showed that the activation of PI3K/AKT and MAPK pathways significantly decreased for DAOY cells after treatment. Finally, our results highlighted that targeting NRP-1 with MR438 could be a potential new strategy to differentiate MB stem cells and could limit medulloblastoma progression.

4.
Carbohydr Res ; 445: 61-64, 2017 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-28412594

RESUMO

α- and ß-C-allylglucopyranosides and hydroxy-, bromo- and azido-derivatives were prepared through allylation at C-1 of methyl 2,3,4,6-tetra-O-benzyl-D-glucopyranoside or 1-O-acetyl-2,3,4,6-tetra-O-benzyl-D-glucopyranose and subsequent chemical modifications of the alkene on the anomeric arm. However, we picked out some discordance between some recent published studies and our results. After a thorough work of characterization and NMR analysis, we unambiguously confirmed α and ß stereochemistry of the two series of compounds and fully described for the first time ß-C-propyl alcohol, bromide and azide of 2,3,4,6-tetra-O-benzyl-D-glucopyranose.


Assuntos
Alcenos/química , Glucose/química , Glucose/síntese química , Azidas/química , Brometos/química , Sequência de Carboidratos , Técnicas de Química Sintética , Estereoisomerismo
5.
Bioorg Med Chem ; 24(21): 5315-5325, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27622745

RESUMO

Neuropilin-1 (NRP-1), a transmembrane glycoprotein acting as a co-receptor of VEGF-A, is expressed by cancer and angiogenic endothelial cells and is involved in the angiogenesis process. Taking advantage of functionalities and stereodiversities of sugar derivatives, the design and the synthesis of carbohydrate based peptidomimetics are here described. One of these compounds (56) demonstrated inhibition of VEGF-A165 binding to NRP-1 (IC50=39µM) and specificity for NRP-1 over VEGF-R2. Biological evaluations were performed on human umbilical vein endothelial cells (HUVECs) through activation of downstream proteins (AKT and ERK phosphorylation), viability/proliferation assays and in vitro measurements of anti-angiogenic abilities.


Assuntos
Carboidratos/farmacologia , Simulação de Acoplamento Molecular , Neuropilina-1/antagonistas & inibidores , Peptidomiméticos/síntese química , Peptidomiméticos/farmacologia , Carboidratos/síntese química , Carboidratos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Estrutura Molecular , Peptidomiméticos/química , Relação Estrutura-Atividade
6.
Carbohydr Res ; 422: 24-33, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26851535

RESUMO

Spiro sugar-isoxazolidines obtained by 1,3-dipolar cycloaddition of activated exo-glycals and nitrones were efficiently functionalized at two sites, i.e. C-4 and C-7, with arginine, arginine mimetics and guanidylated appendages. Two bicyclic sugar derivatives differing by the configuration at C-7 were chosen as model compounds. The small library of peptidomimetics was evaluated toward inhibition of VEGF-A165/neuropilin-1 binding. Unexpected cleavage of C3-C4 bond of isoxazolidine moiety was observed during hydrogenolysis and opened thus a new way toward hemiketal structures which could also find interesting applications as less constrained scaffold.


Assuntos
Carboidratos/química , Desenho de Drogas , Isoxazóis/química , Peptidomiméticos/química , Compostos de Espiro/química , Reação de Cicloadição , Peptidomiméticos/síntese química
7.
Carbohydr Res ; 381: 205-14, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23880224

RESUMO

The thermal and microwave-activated 1,3-dipolar cycloadditions of several α,ß-unsaturated esters derived from d-mannose and chiral nitrones derived from threitol have been studied as a model reaction en route to eleven carbon long chain carbohydrates. Very high facial selectivity is observed for the chiral nitrones whereas the olefin facial selectivity varies with the substrate. The presence of a dioxolane ring α to the olefinic bond is beneficial to the facial selectivity of the olefin whereas a pyranose ring is not. The combination of a d-mannose derivative and a l-threitol-derived nitrone is a matched pair suitable for the synthesis of long chain sugars with nine contiguous chiral centres. Finally complete facial selectivity was observed with exo-glycals which gave a single cycloadduct.


Assuntos
Alcenos/química , Carboidratos/química , Carboidratos/síntese química , Ésteres/química , Óxidos de Nitrogênio/química , Ciclização , Micro-Ondas , Conformação Molecular , Estereoisomerismo
8.
Eur J Med Chem ; 46(9): 3570-80, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21636180

RESUMO

A series of diversely substituted biarylolefins based on carbohydrate and dihydroxyethylene scaffolds were synthesized and evaluated for antiproliferative activity against a panel of human tumor cell lines. Among the thirty-five yet unknown biarylolefins prepared, six displayed potent antiproliferative activities with IC(50) values in the micromolar and submicromolar range. As a new type of antiproliferative agent, the most potent compound 26 showed an IC(50) value of 70 nM against SK-OV3 cell line (ovarian cancer). All the synthesized compounds exhibited a poor or modest tubulin polymerization inhibitory activity suggesting another mode of action for these compounds. Molecular docking simulations to the colchicine binding site of tubulin of representative compounds have been used to explain the lack of activity as inhibitors of tubulin polymerization.


Assuntos
Alcenos/farmacologia , Carboidratos/química , Proliferação de Células/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Alcenos/química , Linhagem Celular Tumoral , Feminino , Humanos , Concentração Inibidora 50 , Tubulina (Proteína)/química , Tubulina (Proteína)/efeitos dos fármacos
9.
Bioorg Med Chem ; 18(9): 3285-98, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20363638

RESUMO

Neuropilin-1 (NRP-1) is a co-receptor of VEGFR(165) and molecules interfering with VEGF(165) binding to NRP-1 seem to be promising candidates as new angiogenesis modulators. Based on the minimal four amino acid sequence of peptidic ligands known to bind NRP-1, we describe here the design, synthesis and biological evaluation of series of original sugar-based peptidomimetics using a C-glycosyl compound, derived from d-gulonolactone, as a scaffold, which was functionalized with side chains of the amino-acids arginine, and tryptophane or threonine. At 100 microM, all compounds exhibited a weak affinity for NRP-1, the most efficient being the bis-guanidinylated compound 32 (IC(50)=92 microM) which could be considered as a new NRP-1 non-peptidic ligand.


Assuntos
Moduladores da Angiogênese , Biomimética , Neuropilina-1 , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Moduladores da Angiogênese/síntese química , Moduladores da Angiogênese/química , Moduladores da Angiogênese/farmacologia , Animais , Carboidratos/síntese química , Carboidratos/química , Carboidratos/farmacologia , Humanos , Concentração Inibidora 50 , Ligantes , Estrutura Molecular , Neuropilina-1/química , Neuropilina-1/metabolismo , Peptídeos/síntese química , Peptídeos/química , Peptídeos/farmacologia , Ligação Proteica/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/metabolismo
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