RESUMO
Two new families of enantiomerically pure carbocyclic nucleoside analogues based on a cyclohexane moiety with five chiral centers and a fused cyclopropyl ring have been synthesized. A highly regio- and stereoselective synthetic approach for the modular construction of the functionalized bicyclo[4.1.0]heptyl azide intermediate 6 has been established. Key steps to achieve this asymmetric synthesis involved highly diastereoselective allylic oxidation and hydroboration reactions. The first family of compounds, 1a,b and 2, presents different natural nucleobases, whereas the second one 3a-e bears functionalized 1,2,3-triazoles. These derivatives have been tested as antiviral agents, and compound 3d has shown to display moderate activity against coxsackie B4 virus.
Assuntos
Heptanos , Nucleosídeos , Nucleosídeos/farmacologia , Antivirais/farmacologia , Estereoisomerismo , TriazóisRESUMO
The enantioselective preparation of the two isomers of 4-hydroxy-2-cyclohexanone derivatives 1a,b was achieved, starting from a common cyclohexenone, through asymmetric transfer hydrogenation (ATH) reactions using bifunctional ruthenium catalysts. From these versatile intermediates, a stereoselective route to a cytosine analogue built on a bicyclo [4.1.0]heptane scaffold is described. Nucleoside kinase activity assays with this cyclopropyl-fused cyclohexane nucleoside, together with other related nucleosides (2a-e), were performed, showing that thymine- and guanine- containing compounds have affinity for herpes simplex virus Type 1 (HSV-1) thymidine kinase (TK) but not for human cytosolic TK-1, thus pointing to their selectivity for herpetic TKs but not cellular TKs.
Assuntos
Herpesvirus Humano 1 , Nucleosídeos , Antivirais , Cicloexanos , Humanos , Timidina QuinaseRESUMO
Bond breaking is an essential process in chemical transformations and the ability of researchers to strategically dictate which bonds in a given system will be broken translates to greater synthetic control. Here, we report extending the concept of selective bond breaking to reticular materials in a new synthetic approach that we call Clip-off Chemistry. We show that bond-breaking in these structures can be controlled at the molecular level; is periodic, quantitative, and selective; is effective in reactions performed in either solid or liquid phases; and can occur in a single-crystal-to-single-crystal fashion involving the entire bulk precursor sample. We validate Clip-off Chemistry by synthesizing two topologically distinct 3D metal-organic frameworks (MOFs) from two reported 3D MOFs, and a metal-organic macrocycle from metal-organic polyhedra (MOP). Clip-off Chemistry opens the door to the programmed disassembly of reticular materials and thus to the design and synthesis of new molecules and materials.
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The combination of the surface-adhesive properties of catechol rings and functional moieties conveying specific properties is very appealing to materials chemistry, but the preparation of catechol derivatives often requires elaborate synthetic routes to circumvent the intrinsic reactivity of the catechol ring. In this work, functional catechols are synthesized straightforwardly by using the bioinspired reaction of several functional thiols with o-benzoquinone. With one exception, the conjugated addition of the thiol takes place regioselectively at the 3-position of the quinone, and is rationalized by DFT calculations. Overall, this synthetic methodology provides a general and straightforward access to functional and chain-extended catechol derivatives, which are later tested with regard to their hydro-/oleophobicity, colloidal stability, fluorescence, and metal-coordinating capabilities in proof-of-concept applications.
Assuntos
Catecóis , Catecóis/química , Metais/química , Compostos de Sulfidrila/química , Propriedades de SuperfícieRESUMO
Allyloxymethyloxymethyl and 4-pentenoyloxymethyl substituents have been used as tethering groups to study the intramolecular [2 + 2] photocycloaddition of chiral 5-substituted 2(5 H)-furanones. The photoreactions proceed in good yield and provide the expected regio- and diastereoselective tricyclic compounds with complementary regioselectivity, which depends on whether the vinyl chain is attached to the furanone by an acetal or an ester linkage. Computational simulations agree with experimental observations and indicate that the origin of the different observed regioselectivity in the intramolecular photochemical reaction of lactones 5 and 6 arises from the relative stability of the initial conformers. The synthetic potential of the enantiomerically pure photoadducts is illustrated by preparing an all- cis 1,2,3-trisubstituted cyclobutane bearing fully orthogonally protected hydroxyl groups.
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The oxidative polymerization of 5,6-dihydroxybenzothiophene (DHBT), the sulfur analog of the key eumelanin building block 5,6-dihydroxyindole (DHI), was investigated to probe the role of nitrogen in eumelanin build-up and properties. Unlike DHI, which gives a typical black insoluble eumelanin polymer on oxidation, DHBT is converted to a grayish amorphous solid (referred to as thiomelanin) with visible absorption and electron paramagnetic resonance properties different from those of DHI melanin. Mass spectrometry experiments revealed gradational mixtures of oligomers up to the decamer level. Quite unexpectedly, nuclear magnetic resonance (NMR) analysis of the early oligomer fractions indicated linear, 4-, and 7-linked structures in marked contrast with DHI, which gives highly complex mixtures of partially degraded oligomers. Density functional theory (DFT) calculations supported the tendency of DHBT to couple via the 4- and 7-positions. These results uncover the role of nitrogen as a major determinant of the structural diversity generated by the polymerization of DHI, and point to replacement by sulfur as a viable entry to regioregular eumelanin-type materials for potential applications for surface functionalization by dip coating.
Assuntos
Melaninas/química , Nitrogênio/química , Polímeros/química , Enxofre/química , Antioxidantes/química , Isomerismo , Modelos Moleculares , Estrutura Molecular , Oxirredução , Polimerização , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Análise EspectralRESUMO
Lanthanide-containing nanoscale particles have been widely explored for various biomedical purposes, however, they are often prone to metal leaching. Here we have created a new coordination polymer (CP) by applying, for the first time, a stable Gd(III) chelate as building block in order to prevent any fortuitous release of free lanthanide(III) ion. The use of the Gd-DOTA-4AmP complex as a design element in the CP allows not only for enhanced relaxometric properties (maximum r1 =16.4â mm(-1) s(-1) at 10â MHz), but also for a pH responsiveness (Δr1 =108 % between pHâ 4 and 6.5), beyond the values obtained for the low molecular weight Gd-DOTA-4AmP itself. The CP can be miniaturised to the nanoscale to form colloids that are stable in physiological saline solution and in cell culture media and does not show cytotoxicity.
RESUMO
A new class of carbocyclic nucleoside analogues built on a bicyclo[4.1.0]heptane scaffold, a perspective novel pseudosugar pattern, have been conceived as anti-HSV agents on the basis of initial protein-ligand docking studies. The asymmetric synthesis of a series of these compounds incorporating different nucleobases has been efficiently completed starting from 1,4-cyclohexanedione.
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Cicloexanonas/química , Heptanos/síntese química , Nucleosídeos/síntese química , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Heptanos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Nucleosídeos/química , EstereoisomerismoRESUMO
A new azobenzene-based photoswitch, 2, has been designed to enable optical control of ionotropic glutamate receptors in neurons via sensitized two-photon excitation with NIR light. In order to develop an efficient and versatile synthetic route for this molecule, a modular strategy is described which relies on the use of a new linear fully protected glutamate derivative stable in basic media. The resulting compound undergoes one-photon trans-cis photoisomerization via two different mechanisms: direct excitation of its azoaromatic unit and irradiation of the pyrene sensitizer, a well-known two-photon sensitive chromophore. Moreover, 2 presents large thermal stability of its cis isomer, in contrast to other two-photon responsive switches relying on the intrinsic nonlinear optical properties of push-pull substituted azobenzenes. As a result, the molecular system developed herein is a very promising candidate for evoking large photoinduced biological responses during the multiphoton operation of neuronal glutamate receptors with NIR light, which require accumulation of the protein-bound cis state of the switch upon repeated illumination.
Assuntos
Compostos Azo/química , Receptores Ionotrópicos de Glutamato/química , Compostos Azo/síntese química , Ligantes , Estrutura Molecular , Neurônios/química , Processos Fotoquímicos , EstereoisomerismoRESUMO
The design and synthesis of a new redox-active ligand combining catechol and pyridine units have allowed the achievement of cobalt-based nanoscale coordination polymer particles in a single-step exhibiting a switchable valence tautomeric behavior and thermal hysteresis. The combination of polymerizing capabilities with redox-active responses in a unique ligand leads to the formation of nanoparticles exhibiting a gradual valence tautomeric interconversion in the 35-370 K temperature range. Using one single ligand to obtain these nanoparticles facilitates possible nanostructure formation methodologies.
RESUMO
Synthetic photochromic compounds can be designed to control a variety of proteins and their biochemical functions in living cells, but the high spatiotemporal precision and tissue penetration of two-photon stimulation have never been investigated in these molecules. Here we demonstrate two-photon excitation of azobenzene-based protein switches and versatile strategies to enhance their photochemical responses. This enables new applications to control the activation of neurons and astrocytes with cellular and subcellular resolution.
Assuntos
Compostos Azo/química , Proteínas/química , Prótons , Compostos Azo/síntese química , Células Cultivadas , Células HEK293 , Humanos , Estrutura Molecular , Processos FotoquímicosRESUMO
The role of the catechol moiety in the adhesive properties of mussel proteins and related synthetic materials has been extensively studied in the last years but still remains elusive. Here, a simplified model approach is presented based on a self-assembled monolayer (SAM) of upward-facing catechols thiol-bound to epitaxial gold substrates. The orientation of the catechol moieties is confirmed by spectroscopy, which also showed lack of significant amounts of interfering o-quinones. Local force-distance curves on the SAM measured by atomic force microscopy (AFM) shows an average adhesion force of 45 nN, stronger than that of a reference polydopamine coating, along with higher reproducibility and less statistical dispersion. This is attributed to the superior chemical and topographical homogeneity of the SAM coating. Catechol-terminated SAMs are also obtained on high-roughness gold substrates that show the ability to assemble magnetic nanoparticles, despite their lack of enhanced adhesion at the molecular level. Finally, the influence of the catechol group on the formation and quality of the SAM is explored both theoretically (molecular dynamics simulations) and experimentally using direct-write AFM lithography.
Assuntos
Materiais Biocompatíveis/química , Catecóis/química , Adesividade , Materiais Revestidos Biocompatíveis/química , Ouro , Indóis/química , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/ultraestrutura , Microscopia de Força Atômica , Simulação de Dinâmica Molecular , Polímeros/química , ImpressãoRESUMO
The interplay of guest encapsulation and release mechanisms in nanoscale metal-organic vehicles and its effect on the drug-delivery kinetics of these materials were investigated through a new multidisciplinary approach. Two rationally-designed molecular guests were synthesized, which consist of a red-fluorescent benzophenoxazine dye covalently tethered to a coordinating catechol group and a protected, non-coordinating catechol moiety. This allowed loading of the guests into compositionally and structurally equivalent coordination polymer particles through distinct encapsulation mechanisms: coordination and mechanical entrapment. The two types of particles delivered their fluorescent cargo with remarkably different kinetic profiles, which could be satisfactorily modeled considering degradation- and diffusion-controlled release processes. This demonstrates that careful selection of the method of guest incorporation into coordination polymer nanoparticles allows selective tuning of the rate of drug delivery from these materials and, therefore, of the time window of action of the encapsulated therapeutic agents.
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A stereodivergent approach to (+)- and (-)-isolineatin using (S)-4-methyl-5-pivaloyloxymethyl-2(5H)-furanone as the single source of asymmetry by exploiting the inherent chirality at the C-5 stereocenter is described.
Assuntos
Furanos/química , Feromônios/síntese química , Piranos/síntese química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Feromônios/química , Piranos/química , EstereoisomerismoRESUMO
The aggregation of wild-type transthyretin (TTR) and over 130 genetic TTR variants underlies a group of lethal disorders named TTR amyloidosis (ATTR). TTR chemical chaperones are molecules that hold great promise to modify the course of ATTR progression. In previous studies, we combined rational design and molecular dynamics simulations to generate a series of TTR selective kinetic stabilizers displaying exceptionally high affinities. In an effort to endorse the previously developed molecules with optimal pharmacokinetic properties, we conducted structural design optimization, leading to the development of PITB. PITB binds with high affinity to TTR, effectively inhibiting tetramer dissociation and aggregation of both the wild-type protein and the two most prevalent disease-associated TTR variants. Importantly, PITB selectively binds and stabilizes TTR in plasma, outperforming tolcapone, a drug currently undergoing clinical trials for ATTR. Pharmacokinetic studies conducted on mice confirmed that PITB exhibits encouraging pharmacokinetic properties, as originally intended. Furthermore, PITB demonstrates excellent oral bioavailability and lack of toxicity. These combined attributes position PITB as a lead compound for future clinical trials as a disease-modifying therapy for ATTR.
Assuntos
Neuropatias Amiloides Familiares , Pré-Albumina , Camundongos , Animais , Pré-Albumina/metabolismo , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/metabolismo , Tolcapona/uso terapêutico , Simulação de Dinâmica MolecularRESUMO
The large tendency of catechol rings to adsorb on surfaces has been studied by STM experiments with molecular resolution combined with molecular-dynamics simulations. The strong adhesion is due to interactions with the surface and solvent effects. Moreover, the thermodynamic control over the differential adsorption of 1 and the nonanoic solvent molecules has been used to induce a new temperature-induced switchable interconversion. Two different phases that differ in their crystal packing and the presence of solvent molecules coexist upon an increase or decrease in the temperature. These results open new insight into the behavior of catechol molecules on surfaces and 2D molecular suprastructures.
Assuntos
Catecóis/química , Microscopia de Tunelamento/métodos , Catecóis/síntese química , Modelos Químicos , Estrutura Molecular , Solventes/química , TermodinâmicaRESUMO
The control of surface wettability with polyphenol coatings has been at the forefront of materials research since the late 1990s, when robust underwater adhesion was linked to the presence of L-DOPA-a catecholic amino acid-in unusually high amounts, in the sequences of several mussel foot proteins. Since then, several successful approaches have been reported, although a common undesired feature of most of them is the presence of a remnant color and/or the intrinsic difficulty in fine-tuning and controlling the hydrophobic character. We report here a new family of functional catechol-based coatings, grounded in the oxidative condensation of readily available pyrocatechol and thiol-capped functional moieties. The presence of at least two additional thiol groups in their structure allows for polymerization through the formation of disulfide bonds. The synthetic flexibility, together with its modular character, allowed us to: (I) develop coatings with applications exemplified by textiles for oil-spill water treatment; (II) develop multifunctional coatings, and (III) fine-tune the WCA for flat and textile surfaces. All of this was achieved with the application of colorless coatings.
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Honey bees are of great economic and ecological importance, but are facing multiple stressors that can jeopardize their pollination efficiency and survival. Therefore, understanding the physiological bases of their stress response may help defining treatments to improve their resilience. We took an original approach to design molecules with this objective. We took advantage of the previous identified neuropeptide allatostatin A (ASTA) and its receptor (ASTA-R) as likely mediators of the honey bee response to a biologically relevant stressor, exposure to an alarm pheromone compound. A first series of ASTA-R ligands were identified through in silico screening using a homology 3D model of the receptor and in vitro binding experiments. One of these (A8) proved also efficient in vivo, as it could counteract two behavioral effects of pheromone exposure, albeit only in the millimolar range. This putative antagonist was used as a template for the chemical synthesis of a second generation of potential ligands. Among these, two compounds showed improved efficiency in vivo (in the micromolar range) as compared to A8 despite no major improvement in their affinity for the receptor in vitro. These new ligands are thus promising candidates for alleviating stress in honey bees.
Assuntos
Neuropeptídeos , Polinização , Animais , Abelhas , Neuropeptídeos/metabolismo , Feromônios/químicaRESUMO
The Ca2+/calmodulin-mediated phosphatase activity of calcineurin (CN) integrates calcium-mediated signaling with gene expression programs involved in the control of essential cellular processes in health and disease, such as the immune response and the pathogenesis of cancer progression and metastasis. In addition, CN is the target of the immunosuppressive drugs cyclosporine A (CsA) and FK-506 which are the cornerstone of immunosuppressant therapy. Unfortunately, long-term administration of these drugs results in severe side effects. Herein, we describe the design, synthesis and evaluation of new synthetic compounds that are capable of inhibiting NFATc activity in a dose-dependent manner, without interfering on CN phosphatase activity. These compounds were designed using the structure-based pharmacophore model of a peptide-derived PxIxIT sequence binding to calcineurin A subunit. Moreover, these compounds inhibit NFATc-dependent cytokine gene expression, secretion and proliferation of human T CD4+ cells. More importantly, compound 5a reduces tumor weight and shows a tendency to reduce tumor angiogenesis in an orthotopic immunocompetent mouse model of triple negative breast cancer, suggesting that 5a has tumor suppressor activity. These findings validate compound 5a as an agent with therapeutic activity against CN-NFATc and highlight its potential as a tool for drug development with therapeutic purposes.
Assuntos
Calcineurina , Neoplasias de Mama Triplo Negativas , Animais , Calcineurina/química , Calcineurina/genética , Calcineurina/metabolismo , Inibidores de Calcineurina , Ciclosporina/farmacologia , Humanos , Camundongos , Fatores de Transcrição NFATC/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Transthyretin amyloidosis (ATTR) is a group of fatal diseases described by the misfolding and amyloid deposition of transthyretin (TTR). Discovering small molecules that bind and stabilize the TTR tetramer, preventing its dissociation and subsequent aggregation, is a therapeutic strategy for these pathologies. Departing from the crystal structure of TTR in complex with tolcapone, a potent binder in clinical trials for ATTR, we combined rational design and molecular dynamics (MD) simulations to generate a series of novel halogenated kinetic stabilizers. Among them, M-23 displays one of the highest affinities for TTR described so far. The TTR/M-23 crystal structure confirmed the formation of unprecedented protein-ligand contacts, as predicted by MD simulations, leading to an enhanced tetramer stability both in vitro and in whole serum. We demonstrate that MD-assisted design of TTR ligands constitutes a new avenue for discovering molecules that, like M-23, hold the potential to become highly potent drugs to treat ATTR.