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1.
Chem Commun (Camb) ; 56(7): 1082-1084, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31894763

RESUMO

G-quadruplexes (G4) are non-canonical nucleic acid structures with important implications in biology. Based on an α-helical fragment of the RHAU helicase that displays high specificity for parallel-stranded G-quadrplexes, herein we demonstrate its head-to-tail cyclization by a high-efficiency ligase. The cyclic peptide exhibits superior stability and binding affinity to a G-quadruplex, and can serve as an excellent investigational tool for chemical biology applications.


Assuntos
RNA Helicases DEAD-box/metabolismo , DNA/metabolismo , Quadruplex G , Fragmentos de Peptídeos/metabolismo , Peptídeos Cíclicos/metabolismo , Células A549 , Ciclização , RNA Helicases DEAD-box/química , DNA/genética , Humanos , Oldenlandia/enzimologia , Fragmentos de Peptídeos/química , Peptídeo Sintases/química , Peptídeos Cíclicos/síntese química , Ligação Proteica , Estabilidade Proteica
2.
Phys Chem Chem Phys ; 21(48): 26301-26310, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31686060

RESUMO

We combine fluorescence up-conversion and time correlated single photon counting experiments to investigate the 5-benzyl uracil excited state dynamics in methanol from 100 fs up to several ns. This molecule has been proposed as a model for DNA/protein interactions. Our results show emission bands at about 310 and 350 nm that exhibit bi-exponential sub-ps decays. Calculations, including solvent effects by a mixed discrete-continuum model, indicate that the Franck Condon region is characterized by significant coupling between the excited states of the benzyl and the uracil moieties, mirrored by the short-lived emission at 310 nm. Two main ground state recovery pathways are identified, both contributing to the 350 nm emission. The first 'photophysical' decay path involves a ππ* excited state localized on the uracil and is connected to the ground electronic state by an easily accessible crossing with S0, accounting for the short lifetime component. Simulations indicate that a possible second pathway is characterized by exciplex formation, with partial benzene → uracil charge transfer character, that may lead instead to photocyclization. The relevance of our results is discussed in view of the photoactivated dynamics of DNA/protein complexes, with implications on their interaction mechanisms.


Assuntos
DNA/química , Proteínas/química , Uracila/química , Ciclização , Teoria da Densidade Funcional , Cinética , Metanol/química , Espectrometria de Fluorescência
3.
Chem Commun (Camb) ; 55(98): 14729-14732, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690911

RESUMO

A palladium-promoted oxidative annulation reaction for the synthesis of structurally diverse naphthoquinone-containing heterocycles has been developed, providing switchable access to 1,2-naphthofuroquinones and densely functionalized cyclobutene-fused 1,4-naphthofuroquinones by selective enol/enolate-directed processes. The synthetic application was extended by late-stage functionalization of an anti-HIV drug. The practical value of 1,2-naphthofuroquinone synthesis was highlighted in endothelial protective lead compound development.


Assuntos
Naftoquinonas/química , Paládio/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Apoptose/efeitos dos fármacos , Catálise , Ciclização , Células Endoteliais da Veia Umbilical Humana , Humanos , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Oxirredução
4.
Org Biomol Chem ; 17(45): 9693-9697, 2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31691700

RESUMO

A series of cyclic Arg-rich mitochondria-penetrating peptides were prepared with variation in the macrocycle size and the chirality of Arg residues. A cyclic heptapeptide was demonstrated to be an efficient mitochondria-specific delivery vector for delivering membrane impermeable peptides.


Assuntos
Membrana Celular/metabolismo , Peptídeos Penetradores de Células/metabolismo , Mitocôndrias/metabolismo , Membrana Celular/química , Sobrevivência Celular , Peptídeos Penetradores de Células/química , Ciclização , Células HeLa , Humanos , Mitocôndrias/química , Conformação Molecular
5.
Top Curr Chem (Cham) ; 377(6): 38, 2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31732819

RESUMO

The concept of merging enamine activation catalysis with transition metal catalysis is an important strategy, which allows for selective chemical transformations not accessible without this combination. The amine catalyst activates the carbonyl compounds through the formation of a reactive nucleophilic enamine intermediate and, in parallel, the transition metal activates a wide range of functionalities such as allylic substrates through the formation of reactive electrophilic π-allyl-metal complex. Since the first report of this strategy in 2006, considerable effort has been devoted to the successful advancement of this technology. In this chapter, these findings are highlighted and discussed.


Assuntos
Aminas/química , Elementos de Transição/química , Alquilação , Alquinos/química , Catálise , Complexos de Coordenação/química , Ciclização , Cetonas/química , Estereoisomerismo
6.
Org Biomol Chem ; 17(39): 8832-8848, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31556900

RESUMO

The reaction of indolizinones with dimethyl acetylenedicarboxylate gave direct access to 3',8a-dihydrocyclopenta[hi]indolizin-8a-ol and 1H-pyrrol-3(2H)-one in good yields. The former skeleton is a precursor to cyclazines with nitrogen on the periphery, a hitherto un-accessed 10-π system. Their formation involves initial [4 + 2] or [8 + 2] modes of cycloadditions; the retro-Diels Alder reaction of the [4 + 2] cycloadduct leads to 1H-pyrrol-3(2H)-one, whereas [8 + 2] addition followed by π-reorganization leads to the azatricyle. Analysis of substituent effects on product distribution showed that electron donating groups on the C3-aryl ring promote the formation of the azatricycle preponderantly. Treatment of one of these azatricycles (3c) with HBF4 led to the formation of the corresponding 10e-aromatic species which was detected by NMR spectroscopy. In addition, formation of the 1H-pyrrol-3(2H)-one skeleton through the normal retro-Diels Alder pathway was employed in the total synthesis of Discoipyrrole C, which is a new lead against lung cancer.


Assuntos
Alquinos/química , Compostos Heterocíclicos com 3 Anéis/química , Pirrolidinonas/química , Cristalografia por Raios X , Ciclização , Compostos Heterocíclicos com 3 Anéis/síntese química , Indolizinas/química , Modelos Moleculares , Estrutura Molecular , Pirrolidinonas/síntese química
7.
Chemistry ; 25(68): 15498-15503, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31518018

RESUMO

A "branching-folding" synthetic strategy that affords a range of diverse cyclic benzo-sulfonamide scaffolds is presented. Whereas different annulation reactions on common ketimine substrates build the branching phase of the scaffold synthesis, a common hydrogenative ring-expansion method, facilitated by an increase of the ring-strain during the branching phase, led to sulfonamides bearing medium-sized rings in a folding pathway. Cell painting assay was successfully employed to identify tubulin targeting sulfonamides as novel mitotic inhibitors.


Assuntos
Sulfonamidas/síntese química , Ciclização , Sulfonamidas/química
8.
Chem Commun (Camb) ; 55(81): 12216-12218, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31552932

RESUMO

acp3U is a hypermodified base that is found in the tRNAs of prokaryotes and eukaryotes and also in the ribosomal RNA of mammals. Its function has so far been unknown but it is speculated that acp3U complexes Mg ions, which may contribute to the stabilization of the RNA structure. As a hypermodified base in which a nucleoside is covalently connected to an amino acid, acp3U is a natural nucleoside between genotype and phenotype and hence is also of particular importance for theories about the origin of life. Herein, we report the development of a phosphoramidite building block and of a solid phase protocol that allows synthesis of RNA containing acp3U.


Assuntos
Nucleosídeos/síntese química , Aminoácidos/química , Sequência de Bases , Ciclização , Isomerismo , Estrutura Molecular , Oligonucleotídeos/química , RNA de Transferência/síntese química , Técnicas de Síntese em Fase Sólida/métodos
9.
Chem Pharm Bull (Tokyo) ; 67(9): 1019-1022, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474725

RESUMO

A novel catalyst system-a combination of the readily available 2,2'-biphenol with the inexpensive, nontoxic, and eco-friendly B(OH)3-promoted the Nazarov cyclization of activated and inactivated divinyl ketones to afford the corresponding cyclopentenones up to 96% yield under, in a cis-selective manner. Compared with the conventional harsh conditions with hazardous reagents, user-friendly method was established with bench-stable and easy-to-handle reagents.


Assuntos
Fenóis/química , Ácidos Borônicos/química , Catálise , Ciclização , Ciclopentanos/química
10.
Chem Commun (Camb) ; 55(70): 10400-10403, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31402360

RESUMO

We report the first pretargeting in vivo study using the Strain-Promoted Sydnone-Alkyne Cycloaadition (SPSAC) reaction. The injection of a fluorine-18 labeled cyclooctyne three days after cetuximab bearing chlorosydnone moieties allowed a significant detection of the tumor by PET imaging suggesting an efficient click reaction inside the tumoral site. With a kinetic constant superior to 300 M-1 s-1, the SPSAC reaction might be an interesting tool, in addition to tetrazine-cyclooctene ligation, for in vivo chemistry.


Assuntos
Alquinos/química , Química Click/métodos , Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons/métodos , Animais , Ciclização , Xenoenxertos , Humanos , Camundongos
11.
Org Biomol Chem ; 17(34): 7995-8000, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31408069

RESUMO

A one-pot three-component tandem reaction involving a key Pictet-Spengler-like annulation step has been developed, providing an efficient method for the synthesis of 3,4-dihydroquinazolines in moderate to good yields from amides, aldehydes, and amines. The multicomponent triflic anhydride mediated reaction tolerates the installation of numerous functional groups, affording extensive diversity about the heterocyclic scaffold.


Assuntos
Furanos/química , Quinazolinas/síntese química , Sulfonamidas/química , Aldeídos/química , Amidas/química , Aminas/química , Ciclização
12.
Chem Commun (Camb) ; 55(71): 10567-10570, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31417998

RESUMO

Macrocyclization of linear peptide precursors using the Petasis borono-Mannich reaction affords a diverse range of macrocycles with an endocyclic amine. Analysis of the corresponding macrocyclic structures underscores that the hydrogen bond between an endocyclic amine and the adjacent amide NH is a powerful control element for conformationally homogenous peptide macrocycles.


Assuntos
Ácidos Borônicos/química , Compostos Macrocíclicos/síntese química , Peptídeos Cíclicos/síntese química , Aldeídos/química , Amidas/química , Aminas/química , Aziridinas/química , Ciclização
13.
Molecules ; 24(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31455006

RESUMO

A short approach to chiral diaza-olefines from protected 2,2'-diamino-1,1'-binaphthyl is presented. Cis- and trans-olefines can be selectively obtained by twofold N-allylation followed by RCM or by bridging a 2,2'-diamino-1,1'-binaphthyl precursor with trans-1,4-dibromo-2-butene. Deprotection afforded cis- and trans-dihydro[1,6]diazecines 1 in 58 and 64% overall yield. The reactivity of the but-2-ene-1,4-diyl fragment was investigated yielding corresponding epoxides, diols, and mono- and dibromo products. In several cases rearrangements and participation of the proximate N-Boc group was observed. In no case could allylic substitution be accomplished. From 13 compounds X-ray structure analyses could be obtained.


Assuntos
Compostos de Epóxi/síntese química , Naftalenos/química , Cristalografia por Raios X , Ciclização , Compostos de Epóxi/química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo
14.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31455019

RESUMO

Tachyplesin I, II and III are host defense peptides from horseshoe crab species with antimicrobial and anticancer activities. They have an amphipathic ß-hairpin structure, are highly positively-charged and differ by only one or two amino acid residues. In this study, we compared the structure and activity of the three tachyplesin peptides alongside their backbone cyclized analogues. We assessed the peptide structures using nuclear magnetic resonance (NMR) spectroscopy, then compared the activity against bacteria (both in the planktonic and biofilm forms) and a panel of cancerous cells. The importance of peptide-lipid interactions was examined using surface plasmon resonance and fluorescence spectroscopy methodologies. Our studies showed that tachyplesin peptides and their cyclic analogues were most potent against Gram-negative bacteria and melanoma cell lines, and showed a preference for binding to negatively-charged lipid membranes. Backbone cyclization did not improve potency, but improved peptide stability in human serum and reduced toxicity toward human red blood cells. Peptide-lipid binding affinity, orientation within the membrane, and ability to disrupt lipid bilayers differed between the cyclized peptide and the parent counterpart. We show that tachyplesin peptides and cyclized analogues have similarly potent antimicrobial and anticancer properties, but that backbone cyclization improves their stability and therapeutic potential.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Sequência de Aminoácidos , Antibacterianos/química , Antibacterianos/farmacologia , Linhagem Celular Tumoral , Ciclização , Estabilidade de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Estrutura Molecular , Espectrometria de Fluorescência , Relação Estrutura-Atividade
15.
Chem Asian J ; 14(22): 4024-4030, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31373769

RESUMO

A diversity-oriented synthesis strategy to produce three types of structurally drug-like N-heterocyclic-fused rings has been developed from abundant biomass-derived d-glucal, aniline and water in a stereoselective manner. The overall transformation which entails a cascade of Ferrier reaction and 4π conrotatory imino-Nazarov cyclization was performed in one-pot allowing convenient preparation of scaffolds of high molecular complexity from relatively simple starting materials. While indoline-fused products were readily accessible using ortho-unsubstituted secondary anilines as substrates, reactions with ortho-hydroxyl-anilines furnished fused 1,4-benzoxazines instead. In both cases, InBr3 acted as the Lewis acid catalyst. By altering InBr3 to Ln(OTf)3 , the indoline-fused products could be further converted into tetrahydroquinoline-fused cyclopentenones via ensuing retro-ene rearrangement.


Assuntos
Gluconato de Cálcio/química , Compostos de Anilina/química , Catálise , Complexos de Coordenação/química , Ciclização , Indóis/química , Quinolinas/química , Estereoisomerismo
16.
Chemistry ; 25(58): 13309-13317, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31328310

RESUMO

The synthesis of the protected form of 2-methylthio-N6 -threonylcarbamoyl adenosine (ms2 t6 A) was developed starting from adenosine or guanosine by using the optimized carbamate method and, for the first time, an isocyanate route. The hypermodified nucleoside was subsequently transformed into the protected ms2 t6 A-phosphoramidite monomer and used in a large-scale synthesis of the precursor 17nt ms2 t6 A-oligonucleotide (the anticodon stem and loop fragment of tRNALys from T. brucei). Finally, stereochemically secure ms2 t6 A→ms2 ct6 A cyclization at the oligonucleotide level efficiently afforded a tRNA fragment bearing the ms2 ct6 A unit. The applied post-synthetic approach provides two sequentially homologous ms2 t6 A- and ms2 ct6 A-oligonucleotides that are suitable for further comparative structure-activity relationship studies.


Assuntos
Adenosina/análogos & derivados , Oligorribonucleotídeos/síntese química , RNA de Transferência/química , Treonina/análogos & derivados , Adenosina/química , Sequência de Bases , Carbamatos/química , Ciclização , Guanosina/química , Isocianatos/química , Conformação de Ácido Nucleico , Compostos Organofosforados/química , Relação Estrutura-Atividade , Treonina/síntese química , Treonina/química
17.
Molecules ; 24(14)2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31323851

RESUMO

Single-chain Fv (scFv) antibodies are recombinant proteins in which the variable regions of the heavy chain (VH) and light chain (VL) are connected by a short flexible polypeptide linker. ScFvs have the advantages of easy genetic manipulation and low-cost production using Escherichia coli compared with monoclonal antibodies, and are thus expected to be utilized as next-generation medical antibodies. However, the practical use of scFvs has been limited due to low homogeneity caused by their aggregation propensity mediated by inter-chain VH-VL interactions. Because the interactions between the VH and VL domains of antibodies are generally weak, individual scFvs are assumed to be in equilibrium between a closed state and an open state, in which the VH and VL domains are assembled and disassembled, respectively. This dynamic feature of scFvs triggers the formation of dimer, trimer, and larger aggregates caused by the inter-chain VH-VL interactions. To overcome this problem, the N-terminus and C-terminus were herein connected by sortase A-mediated ligation to produce a cyclic scFv. Open-closed dynamics and aggregation were markedly suppressed in the cyclic scFv, as judged from dynamic light scattering and high-speed atomic force microscopy analyses. Surface plasmon resonance and differential scanning fluorometry analysis revealed that neither the affinity for antigen nor the thermal stability was disrupted by the scFv cyclization. Generality was confirmed by applying the present method to several scFv proteins. Based on these results, cyclic scFvs are expected to be widely utilized in industrial and therapeutic applications.


Assuntos
Cadeias Pesadas de Imunoglobulinas/química , Cadeias Leves de Imunoglobulina/química , Região Variável de Imunoglobulina/química , Anticorpos de Cadeia Única/química , Varredura Diferencial de Calorimetria , Ciclização , Difusão Dinâmica da Luz , Humanos , Cadeias Pesadas de Imunoglobulinas/metabolismo , Cadeias Leves de Imunoglobulina/metabolismo , Região Variável de Imunoglobulina/metabolismo , Microscopia de Força Atômica , Agregados Proteicos , Ligação Proteica , Anticorpos de Cadeia Única/metabolismo , Ressonância de Plasmônio de Superfície
18.
Nat Commun ; 10(1): 3234, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324800

RESUMO

Rearrangement reactions have attracted considerable interest over the past decades due to their high bond-forming efficiency and atom economy in the construction of complex organic architectures. In contrast to the well-established [3,3]-rearrangement, [1,3] O-to-C rearrangement has been far less vigorously investigated, and stereospecific [1,3]-rearrangement is extremely rare. Here, we report a metal-free intramolecular hydroalkoxylation/[1,3]-rearrangement, leading to the practical and atom-economical assembly of various valuable medium-sized lactams with wide substrate scope and excellent diastereoselectivity. Moreover, such an asymmetric cascade cyclization has also been realized by chiral Brønsted acid-catalyzed kinetic resolution. In addition, biological tests reveal that some of these medium-sized lactams displayed their bioactivity as antitumor agents against melanoma cells, esophageal cancer cells and breast cancer cells. A mechanistic rationale for the reaction is further supported by control experiments and theoretical calculations.


Assuntos
Alcenos/química , Alquinos/química , Ciclização , Lactamas/química , Metais/química , Catálise , Cinética , Lactamas/síntese química , Modelos Químicos , Estrutura Molecular , Estereoisomerismo
19.
Molecules ; 24(14)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31331097

RESUMO

Three (R)-BINOL-based macrocyclic receptors obtained via double-amidation reaction were used for chiral recognition of four anions derived from α-hydroxy and α-amino acids. The structural factors of hosts and guests that affect chiral recognition processes were also investigated, indicating that the proper geometry of both receptor and guest molecules plays a crucial role in effective enantio-discrimination.


Assuntos
Ânions/química , Ácidos Carboxílicos/química , Compostos Macrocíclicos/química , Naftalenos/química , Ciclização , Ligações de Hidrogênio , Estrutura Molecular , Análise Espectral
20.
J Pept Sci ; 25(8): e3177, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31317614

RESUMO

Thermal treatment of short-chain oligopeptides is able to initiate the process of their self-assembly with the formation of organic nanostructures with unique properties. On the other hand, heating can lead to a chemical reaction with the formation of new substances with specific properties and ability to form structures with different morphology. Therefore, in order to have a desired process, researcher needs to find its temperature range. In the present work, cyclization of L -isoleucyl-L -alanine dipeptide in the solid state upon heating was studied. Kinetic parameters of this reaction were estimated within the approaches of the nonisothermal kinetics. The correlation between side chain structure of dipeptides and temperature of their cyclization in the solid state was found for the first time. This correlation may be used to predict the temperature, at which dipeptide self-assembly changes to chemical reaction. The differences in self-assembly of linear and cyclic dipeptides were demonstrated using atomic force microscopy. The effect of dipeptide concentration in a source solution and an organic solvent used on self-assembly of dipeptides was shown. The new information obtained on the thermal properties and self-assembly of linear and cyclic forms of L -isoleucyl-L -alanine may be useful for the design of new nanomaterials based on oligopeptides, as well as for the synthesis of cyclic oligopeptides.


Assuntos
Alanina/química , Dipeptídeos/síntese química , Isoleucina/química , Temperatura Ambiente , Ciclização , Dipeptídeos/química , Cromatografia Gasosa-Espectrometria de Massas , Cinética , Conformação Molecular
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