RESUMO
Biofilm formation is one of main causes of bacterial antimicrobial resistance infections. It is known that the soluble lectins LecA and LecB, produced by Pseudomonas aeruginosa, play a key role in biofilm formation and lung infection. Bacterial lectins are therefore attractive targets for the development of new antibiotic-sparing anti-infective drugs. Building synthetic glycoconjugates for the inhibition and modulation of bacterial lectins have shown promising results. Light-sensitive lectin ligands could allow the modulation of lectins activity with precise spatiotemporal control. Despite the potential of photoswitchable tools, few photochromic lectin ligands have been developed. We have designed and synthesized several O- and S-galactosyl azobenzenes as photoswitchable ligands of LecA and evaluated their binding affinity with isothermal titration calorimetry. We show that the synthesized monovalent glycoligands possess excellent photophysical properties and strong affinity for targeted LecA with K d values in the micromolar range. Analysis of the thermodynamic contribution indicates that the Z-azobenzene isomers have a systematically stronger favorable enthalpy contribution than the corresponding E-isomers, but due to stronger unfavorable entropy, they are in general of lower affinity. The validation of this proof-of-concept and the dissection of thermodynamics of binding will help for the further development of lectin ligands that can be controlled by light.
RESUMO
Radical ring-opening polymerization (rROP) of cyclic ketene acetals (CKAs) with traditional vinyl monomers allows the synthesis of degradable vinyl copolymers. However, since the most commonly used CKAs are hydrophobic, most degradable vinyl copolymers reported so far degrade very slowly by hydrolysis under physiological conditions (phosphate-buffered saline, pH 7.4, 37 °C), which can be detrimental for biomedical applications. Herein, to design advanced vinyl copolymers by rROP with high CKA content and enhanced degradation profiles, we reported the copolymerization of 2-methylene-1,3,6-trioxocane (MTC) as a CKA with vinyl ether (VE) or maleimide (MI) derivatives. By performing a point-by-point comparison between the MTC/VE and MTC/MI copolymerization systems, and their counterparts based on 2-methylene-1,3-dioxepane (MDO) and 5,6-benzo-2-methylene-1,3-dioxepane (BMDO), we showed negligible impact on the macromolecular characteristics and similar reactivity ratios, suggesting successful substitution of MDO and BMDO by MTC. Interestingly, owing to the hydrophilicity of MTC, the obtained copolymers exhibited a faster hydrolytic degradation under both accelerated and physiological conditions. We then prepared MTC-based glycopolymers, which were formulated into surfactant-free nanoparticles, exhibiting excellent colloidal stability up to 4 months and complete degradation under enzymatic conditions. Importantly, MTC-based glyconanoparticles also showed a similar cytocompatibility toward two healthy cell lines and a much stronger lectin affinity than MDO-based glyconanoparticles.
Assuntos
Acetais , Nanopartículas , Hidrólise , Acetais/química , Polímeros/química , Nanopartículas/química , Interações Hidrofóbicas e HidrofílicasRESUMO
Here we report a simple electrochemical route towards the synthesis of S-arylated peptides by a site selective coupling of peptides with aryl halides under base free conditions. This approach demonstrates the power of electrochemistry to access both highly complex peptide conjugates and cyclic peptides.
Assuntos
Cisteína , Níquel , Níquel/química , Catálise , Peptídeos , Peptídeos CíclicosRESUMO
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/complicaçõesRESUMO
A small library of degradable polyester-like glycopolymers was successfully prepared by the combination of radical ring-opening copolymerization of 2-methylene-1,3-dioxepane as a cyclic ketene acetal (CKA) with vinyl ether (VE) derivatives and a Pd-catalyzed thioglycoconjugation. The resulting thioglycopolymers were formulated into self-stabilized thioglyconanoparticles, which were stable up to 4 months and were enzymatically degraded. Nanoparticles and their degradation products exhibited a good cytocompatibility on two healthy cell lines. Interactions between thioglyconanoparticles and lectins were investigated and highlighted the presence of both specific carbohydrate/lectin interactions and nonspecific hydrophobic interactions. Fluorescent thioglyconanoparticles were also prepared either by encapsulation of Nile red or by the functionalization of the polymer backbone with rhodamine B. Such nanoparticles were used to prove the cell internalization of the thioglyconanoparticles by lung adenocarcinoma (A549) cells, which underlined the great potential of P(CKA-co-VE) copolymers for biomedical applications.
Assuntos
Nanopartículas , Acetais/química , Éteres Cíclicos , Nanopartículas/química , Polimerização , Polímeros/químicaRESUMO
A series of 2,4-di-arylated tropane derivatives was synthesized through a site-selective palladium-catalyzed ß-C(sp3)-H di-arylation process. This type of structure has been scarcely reported in literature. They nevertheless represent an interesting class of biologically relevant molecules as illustrated by the observed activity at the micromolecular level of eight derivatives toward human colorectal cancer cell line HCT116.
Assuntos
Paládio , Tropanos , Humanos , Paládio/química , Catálise , Estrutura MolecularRESUMO
In the context of our SAR study concerning 6BrCaQ analogues as C-terminal Hsp90 inhibitors, we designed and synthesized a novel series of 3-(heteroaryl)quinolin-2(1H), of types 3, 4, and 5, as a novel class of analogues. A Pd-catalyzed Liebeskind-Srogl cross-coupling was developed as a convenient approach for easy access to complex purine architectures. This series of analogues showed a promising biological effect against MDA-MB231 and PC-3 cancer cell lines. This study led to the identification of the best compounds, 3b (IC50 = 28 µM) and 4e, which induce a significant decrease of CDK-1 client protein and stabilize the levels of Hsp90 and Hsp70 without triggering the HSR response.
Assuntos
Proteínas de Choque Térmico HSP90RESUMO
Transition-metal-catalyzed C-H functionalization and photoredox nickel dual catalysis have emerged as innovative and powerful avenues for the synthesis of C-branched glycosides. These two concepts have been recently established and provide efficient and mild methods for accessing a series of valuable complex C-branched glycosides of great interest. Herein, recent developments in the synthesis of C-branched aryl/alkenyl/alkyl glycosides through these two approaches are highlighted.
RESUMO
We have discovered a new mode of reactivity of 1-thiosugars in the presence of Cu(II) or Co(II) for a stereoselective O-glycosylation reaction. The process involves the use of a catalytic amount of Cu(acac)2 or Co(acac)2 and Ag2CO3 as an oxidant in α,α,α-trifluorotoluene. Moreover, this protocol turned out to have a broad scope, allowing the preparation of a wide range of complex substituted O-glycoside esters in good to excellent yields with an exclusive 1,2-trans-selectivity. The late-stage modification of pharmaceuticals by this method was also demonstrated. To obtain a closer insight into the reaction mechanism, cyclic voltammetry was performed.
RESUMO
Direct and practical anomeric O-arylation of sugar lactols with substituted arylboronic acids has been established. Using copper catalysis at room temperature under an air atmosphere, the protocol proved to be general, and a variety of aryl O-glycosides have been prepared in good to excellent yields. Furthermore, this approach was extended successfully to unprotected carbohydrates, including α-mannose, and it was demonstrated here how the interaction between carbohydrates and boronic acids can be combined with copper catalysis to achieve selective anomeric O-arylation.
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An efficient method for the thioglycoconjugation of iodinated oligonucleotides by Buchwald-Hartwig-Migita cross-coupling under mild conditions is reported. The method enables divergent synthesis of many different functionalized thioglycosylated ODNs in good yields, without affecting the integrity of the other A, C, and G nucleobases.
Assuntos
Oligonucleotídeos/química , Compostos de Sulfidrila/química , Catálise , Cromatografia Líquida de Alta Pressão , Glicosilação , Paládio/química , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A convergent total synthesis of MK-801 has been achieved. Key synthetic transformations include a multicomponent Barbier-type reaction to construct the α-branched amine, a selective Heck α-coupling tactic to generate the exocyclic alkene skeleton, and a late-stage intramolecular hydroamination reaction between the exocyclic alkene and the secondary protected amine. The efficacy of this method was demonstrated by the synthesis of two news analogues substituted on the aromatic rings.
Assuntos
Maleato de Dizocilpina/síntese química , Maleato de Dizocilpina/química , Estrutura MolecularRESUMO
Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with α- or ß-3-iodo-N-glycosylquinolin-2-ones has been accomplished under mild and operationally simple reaction conditions through the use of a Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of α- or ß-mono-, di-, and poly-thiosugar derivatives to efficiently synthesize a series of α- or ß-N,S-bis-glycosyl quinolin-2-ones, which are difficult to synthesize by classical methods.
Assuntos
Paládio/química , Fosfinas/química , Quinolonas/síntese química , Xantenos/química , Catálise , Halogenação , Estrutura Molecular , Acoplamento Oxidativo , Quinolonas/químicaRESUMO
New applications of Pd-catalyzed coupling reactions (Suzuki-Miyaura, Sonogashira, and Stille-Migita coupling) for post-conjugation of nucleic acids have been developed recently. Breakthroughs in this area might now pave the way for the development of sophisticated DNA probes, which might be of great interest in chemical biology, nanotechnology, and bioanalysis, as well as in diagnostic domains.
Assuntos
Sondas de Ácido Nucleico/química , Paládio/química , Catálise , Coloração e RotulagemRESUMO
Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with 2-iodoglycals has been accomplished under mild and operationally simple reaction conditions through the use of Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of α- or ß-mono-, di-, and polythiosugar derivatives to synthesize efficiently a series of (1 â 2)-S-linked thiosaccharides and S-linked glycoconjugates, which are difficult to synthesize by classical methods.
RESUMO
An efficient thioglycosylation of C(sp2 )-H bonds with thiosugars has been established for the first time. Using only Cu(OAc)2 â 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.
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 , TemperaturaRESUMO
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.
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.
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.