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Nonpolar solvents commonly used in scanning tunneling microscope-based break junction measurements exhibit hazards and relatively low boiling points (bp) that limit the scope of solution experiments at elevated temperatures. Here we show that low toxicity, ultrahigh bp solvents such as bis(2-ethylhexyl) adipate (bp = 417 °C) and squalane (457 °C) can be used to probe molecular junctions at ≥100 °C. With these, we extend solvent- and temperature-dependent conductance trends for junction components such as 4,4'-bipyridine and thiomethyl-terminated oligophenylenes and reveal the gold snapback distance is larger at 100 °C due to increased surface atom mobility. We further show the rate of surface transmetalation and homocoupling reactions using phenylboronic acids increases at 100 °C, while junctions comprising anticipated boroxine condensation products form only at room temperature in an anhydrous glovebox atmosphere. Overall, this work demonstrates the utility of low vapor pressure solvents for the comprehensive characterization of junction properties and chemical reactivity at the single-molecule limit.
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Directional bonding strategies guide the design of complex molecular architectures, yet challenges arise due to emergent behavior. Rigid structures face geometric constraints and sensitivity to mismatches, hindering the efficient assembly of molecular organic cages (MOCs). Harnessing intramolecular non-covalent interactions offers a promising solution, broadening geometrical possibilities and enhancing adaptability to boost assembly yields. However, identifying these interactions remains challenging, with their full potential sometimes latent until final assembly. This study explores these challenges by synthesizing boronic acid tripods with varied oxygen positions at the tripodal feet and investigating their role in assembling tetrahedral boronate MOCs. Our results reveal substantial differences in the assembly efficiency among tripods. While the building blocks with oxygen in the benzylic position relative to the central aromatic ring form the MOCs in high yields, those with the oxygen atom directly bound to the central aromatic ring, only yield traces. Through X-ray crystallography and DFT analyses, we elucidate how intramolecular interactions profoundly influence the geometry of the building blocks and cages in a relay-like fashion, highlighting the importance of considering intramolecular interactions in the rational design of (supra)molecular architectures.
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Penicillin-binding proteins (PBPs) contribute to bacterial cell wall biosynthesis and are targets of antibacterial agents. Here, we investigated PBP1b inhibition by boronic acid derivatives. Chemical starting points were identified by structure-based virtual screening and aliphatic boronic acids were selected for further investigations. Structure-activity relationship studies focusing on the branching of the boron-connecting carbon and quantum mechanical/molecular mechanical simulations showed that reaction barrier free energies are compatible with fast reversible covalent binding and small or missing reaction free energies limit the inhibitory activity of the investigated boronic acid derivatives. Therefore, covalent labelling of the lysine residue of the catalytic dyad was also investigated. Compounds with a carbonyl warhead and an appropriately positioned boronic acid moiety were shown to inhibit and covalently label PBP1b. Reversible covalent labelling of the catalytic lysine by imine formation and the stabilisation of the imine by dative N-B bond is a new strategy for PBP1b inhibition.
Assuntos
Lisina , Serina , Proteínas de Ligação às Penicilinas/química , Proteínas de Ligação às Penicilinas/metabolismo , Ácidos Borônicos/farmacologia , Antibacterianos/farmacologia , IminasRESUMO
In photo-induced olefin synthesis, the photocatalysts with high triplet energy could cause the isomerization of olefins. This study demonstrates a new quinoxalinone photocatalytic system for highly stereoselective alkenes preparation from alkenyl sulfones and alkyl boronic acids. Our photocatalyst could not convert the thermodynamically favored E-olefin to Z-olefin, guaranteeing the high E-configuration selectivity of the reaction. There is weak interaction between boronic acids and quinoxalinone according to NMR experiments, probably decreasing the oxidation potential of boronic acids. This system can be further extended to the allyl and alkynyl sulfones to give corresponding alkenes and alkynes.
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The assembly of aryl boronic acids B with quinones Q into columnar mixed stacked materials, as previously observed in the solid-state, has been here subjected to a detailed theoretical analysis focusing on the properties of the isolated synthons (HOMO-LUMO energies, electron affinity, ionization potential, reorganization hole/electron energies, partial Hirshfeld atomic charges and conformation stabilities) as well as those of the 1 : 1 adducts (Hirshfeld analysis, IRI surfaces, Hirshfeld atomic charges, hydrogen bond and slipped stacked π-π contributions). The overall picture obtained throught this study shows an intricate pattern of interconnected factors contributing to the formation and stability of the Bx Qy adducts, and it unveils the importance of parameters such as HOMO-LUMO gap, polarization and charge transfer, in addition to the more evident hydrogen bond and slipped-stacked π-π interactions in the formation of 1 : 1 adducts. An explanation has been also given for the presence in some Bx Qy adducts of the rare anti-anti conformation for the BO-H group with respect to the most studied and common anti-syn conformation.
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Boronic acids are essential building blocks used for the synthesis of bioactive molecules, the generation of chemical libraries and the exploration of structure-activity relationships. As a result, more than ten thousand boronic acids are commercially available. Medicinal chemists are therefore facing a challenge; which of them should they select to maximize information obtained by the synthesis of new target molecules. The present article aims to help them to make the right choices. The boronic acids used frequently in the synthesis of bioactive molecules were identified by mining several large molecular and reaction databases and their properties were analyzed. Based on the results a diverse set of boronic acids covering well the bioactive chemical space was selected and is suggested as a basis for library design for the efficient exploration of structure-activity relationships. A Boronic Acid Navigator web tool which helps chemists to make their own selection is also made available at https://bit.ly/boronics.
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Ácidos Borônicos , Bibliotecas de Moléculas Pequenas , Ácidos Borônicos/química , Bases de Dados Factuais , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Various boron-containing isocyanides have been efficiently synthesized from the corresponding enantiopure ß-substituted ß-amino boronic acid pinacol esters, without need for protecting group interconversion, through a two-step, purification-free procedure. They were employed in a variety of isocyanide-based multicomponent reactions, proving to be reliable components for all of them and allowing the efficient synthesis of unprecedented, boron-containing peptidomimetics and heteroatom-rich small molecules, including biologically relevant cyclic boronates. Jointing together the ß-amido boronic acid moiety, deriving from the isocyanide component, with prominent pharmacophoric rings emerging from the multicomponent process, a successful application of the molecular hybridization concept could be realized.
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Cianetos , Peptidomiméticos , Boro , Ésteres , Ácidos BorônicosRESUMO
The COVID-19 pandemic has given a strong impetus to the search for antivirals active on SARS-associated coronaviruses. Over these years, numerous vaccines have been developed and many of these are effective and clinically available. Similarly, small molecules and monoclonal antibodies have also been approved by the FDA and EMA for the treatment of SARS-CoV-2 infection in patients who could develop the severe form of COVID-19. Among the available therapeutic tools, the small molecule nirmatrelvir was approved in 2021. It is a drug capable of binding to the Mpro protease, an enzyme encoded by the viral genome and essential for viral intracellular replication. In this work, by virtual screening of a focused library of ß-amido boronic acids, we have designed and synthesized a focused library of compounds. All of them were biophysically tested by microscale thermophoresis, attaining encouraging results. Moreover, they also displayed Mpro protease inhibitory activity, as demonstrated by performing enzymatic assays. We are confident that this study will pave the way for the design of new drugs potentially useful for the treatment of SARS-CoV-2 viral infection.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/metabolismo , Pandemias , Inibidores de Proteases/química , Antivirais/farmacologia , Simulação de Acoplamento MolecularRESUMO
The Petasis reaction, also called the Petasis Borono-Mannich reaction, is a multicomponent reaction that couples a carbonyl derivative, an amine and boronic acids to yield substituted amines. The reaction proceeds efficiently in the presence or absence of a specific catalyst and solvent. By employing this reaction, a diverse range of chiral derivatives can easily be obtained, including α-amino acids. A broad substrate scope, high yields, distinct functional group tolerance and the availability of diverse catalytic systems constitute key features of this reaction. In this review article, attention has been drawn toward the recently reported methodologies for executing the Petasis reaction to produce structurally simple to complex aryl/allyl amino scaffolds.
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Small molecule drugs that covalently bind irreversibly to their target proteins have several advantages over conventional reversible inhibitors. They include increased duration of action, less-frequent drug dosing, reduced pharmacokinetic sensitivity, and the potential to target intractable shallow binding sites. Despite these advantages, the key challenges of irreversible covalent drugs are their potential for off-target toxicities and immunogenicity risks. Incorporating reversibility into covalent drugs would lead to less off-target toxicity by forming reversible adducts with off-target proteins and thus reducing the risk of idiosyncratic toxicities caused by the permanent modification of proteins, which leads to higher levels of potential haptens. Herein, we systematically review electrophilic warheads employed during the development of reversible covalent drugs. We hope the structural insights of electrophilic warheads would provide helpful information to medicinal chemists and aid in designing covalent drugs with better on-target selectivity and improved safety.
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The transition-metal-catalyzed carbonylation reaction is a useful approach for ketone synthesis. However, it is often problematic to use exogenous carbonyl reagents, such as gaseous carbon monoxide. In this manuscript, we report a novel palladium-catalyzed coupling reaction of gem-difluoroalkenes and aryl boronic acids that yields bioactive indane-type ketones with an all-carbon α-quaternary center. Characterization and stoichiometric reactions of the key intermediates RCF2 PdII support a water-induced defluorination and cross-coupling cascade mechanism. The vinyl difluoromethylene motif serves as an in situ carbonyl precursor which is unprecedented in transition-metal-catalyzed coupling reactions. It is expected to raise broad research interest from the perspectives of ketone synthesis, fluoroalkene functionalization, and rational design of new synthetic protocols based on the unique reactivity of difluoroalkyl palladium(II) species.
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Ácidos Borônicos , Paládio , Catálise , Água , CetonasRESUMO
Liposomes are effective therapeutic nanocarriers due to their ability to encapsulate and enhance the pharmacokinetic properties of a wide range of drugs and diagnostic agents. A primary area in which improvement is needed for liposomal drug delivery is to maximize the delivery of these nanocarriers to cells. Cell membrane glycans provide exciting targets for liposomal delivery since they are often densely clustered on cell membranes and glycan overabundance and aberrant glycosylation patterns are a common feature of diseased cells. Herein, we report a liposome platform incorporating bis-boronic acid lipids (BBALs) to increase valency in order to achieve selective saccharide sensing and enhance cell surface recognition based on carbohydrate binding interactions. In order to vary properties, multiple BBALs (1 a-d) with variable linkers in between the binding units were designed and synthesized. Fluorescence-based microplate screening of carbohydrate binding showed that these compounds exhibit varying binding properties depending on their structures. Additionally, fluorescence microscopy experiments indicated enhancements in cellular association when BBALs were incorporated within liposomes. These results demonstrate that multivalent BBALs serve as an exciting glycan binding liposome system for targeted delivery.
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Ácidos Borônicos , Lipossomos , Lipossomos/química , Ácidos Borônicos/química , Carboidratos , Membrana Celular , Polissacarídeos , Sistemas de Liberação de Medicamentos/métodosRESUMO
Boronic acids are Lewis acids that exist in equilibrium with boronate forms in aqueous solution. Here we experimentally and computationally investigated the Lewis acidity of 2,6-diarylphenylboronic acids; specially designed phenylboronic acids that possess two flanking aromatic rings with tunable aromatic character. Hammett analysis of 2,6-diarylphenylboronic acids reveals that their Lewis acidity remains unchanged upon the introduction of EWG/EDG at the distant para position of the flanking aromatic rings. Structural and computational studies demonstrate that polar-π interactions and solvation effects contribute to the stabilization of boronic acids and boronate forms by aromatic rings. Our physical-organic chemistry work highlights that boronic acids and boronates can be stabilized by aromatic systems, leading to an important molecular knowledge for rational design and development of boronic acid-based catalysts and inhibitors of biomedically important proteins.
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Ácidos Borônicos , Ácidos de Lewis , Ácidos Borônicos/química , Proteínas/químicaRESUMO
An expedient ex-situ generation of difluoroiodomethane (DFIM) and its immediate use in a Pd-catalyzed difluoromethylation of aryl boronic acids and ester derivatives in a two-chamber reactor is reported. Heating a solution of bromodifluoroacetic acid with sodium iodide in sulfolane proved to be effective for the generation of near stoichiometric amounts of DFIM for the ensuing catalytic coupling step. A two-step difluoromethylation of aryl (pseudo)halides with tetrahydroxydiboron as a low-cost reducing agent, both promoted by Pd catalysis, proved effective to install this fluorine-containing C1 group onto several pharmaceutically relevant molecules. Finally, the method proved adaptable to deuterium incorporation by simply adding D2 O to the DFIM-generating chamber.
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Ácidos Borônicos , Paládio , Catálise , Ésteres , FlúorRESUMO
Over the last decades, boron and nucleic acids chemistries have gained a lot of attention for biological, medicinal and analytical applications. Our laboratory has a long-standing interest in both chemistries and owing to the ability of boronic acids to react with cis-diol function in aqueous media we developed over the years a variety of applications ranging from molecular recognition and sensing to the development of reversible dynamic systems in which the natural phosphodiester linkage was replaced by a boronate. In this account, we summarize research results from our group from our preliminary studies on molecular recognition of ribonucleosides to the dynamic assembly of functional DNAzymes. In particular, the various parameters influencing the dynamic nature of these reversible covalent bonds able to respond to external stimuli are discussed. Finally, current challenges and opportunities for boron-based nucleic acids are also addressed.
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Ácidos Borônicos , Ácidos Nucleicos , Boro , Ácidos Borônicos/química , Ácidos Nucleicos/químicaRESUMO
We have recently highlighting the role of spiroisoxazoline arteannuin B derivatives in mediating proinflammatory cytokines like IL-6, TNfα and NO in vitro. In the present study, a series of new ß-arylated arteannuin B analogues were synthesized through coupling with arylboroic acids and evaluated for their in vitro cytotoxic activity in a panel of six cancer cell lines. The binding efficiency was verified by docking of the original ligand within the active site of ATPase domain of GRP78 (PDB ID: 3LDL) at a resolution of 2.30 Å with the score energy of -8.07 kcal/mol. Among the new compounds 3a, 3b, 3d, 3i, 3j and 3n displayed potent cytotoxic potential with an IC50 from 2 to 18 µM and compound 3i was proven to be the most potent cytotoxic and anti-proliferative compound of all the six distinct cell lines. Compound 3i exhibited promising apoptosis inducing potential in breast cancer cells and stalled their wound healing properties and was effective in blocking the migration of cancer cells.
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Antineoplásicos , Neoplasias Pulmonares , Antineoplásicos/química , Artemisininas , Ácidos Borônicos/farmacologia , Catálise , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Paládio , Relação Estrutura-AtividadeRESUMO
Antibacterial resistance towards the ß-lactam (BL) drugs is now ubiquitous, and there is a major global health concern associated with the emergence of new ß-lactamases (BLAs) as the primary cause of resistance. In addition to the development of new antibacterial drugs, ß-lactamase inhibition is an alternative modality that can be implemented to tackle this resistance channel. This strategy has successfully revitalized the efficacy of a number of otherwise obsolete BLs since the discovery of the first ß-lactamase inhibitor (BLI), clavulanic acid. Over the years, ß-lactamase inhibition research has grown, leading to the introduction of new synthetic inhibitors, and a few are currently in clinical trials. Of note, the 1, 6-diazabicyclo [3,2,1]octan-7-one (DBO) scaffold gained the attention of researchers around the world, which finally culminated in the approval of two BLIs, avibactam and relebactam, which can successfully inhibit Ambler class A, C, and D ß-lactamases. Boronic acids have shown promise in coping with Ambler class B ß-lactamases in recent research, in addition to classes A, C, and D with the clinical use of vaborbactam. This review focuses on the further developments in the synthetic strategies using DBO as well as boronic acid derivatives. In addition, various other potential serine- and metallo- ß-lactamases inhibitors that have been developed in last few years are discussed briefly as well. Furthermore, binding interactions of the representative inhibitors have been discussed based on the crystal structure data of inhibitor-enzyme complex, published in the literature.
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Compostos Azabicíclicos , beta-Lactamases , Adaptação Psicológica , Antibacterianos/química , Antibacterianos/farmacologia , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/químicaRESUMO
Pd0 catalysts featuring phosphorus-based monodentate ligands can detour the reactivity of carbonyl-tethered alkylidenecyclopropanes (ACPs) from standard (3+2) cycloadditions towards tandem cycloisomerization/cross-coupling processes. This new reactivity lies on the formation of key π-allyl oxapalladacyclic intermediates, which are subsequently trapped with external nucleophilic partners, instead of undergoing canonical C-O reductive eliminations. Importantly, the use of imine-tethered ACP's is also feasible. Therefore, the method provides a straightforward and stereoselective entry to a wide variety of highly functionalized cyclic alcohols and amines.
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The reactions of N-sulfonylhydrazones derived from cyclic ketones with γ-azidopropylboronic acid and 2-(azidomethyl)phenylboronic acid give rise to spirocyclic pyrrolidines and spiroisoindolines, respectively. The reactions proceed without the need of any transition-metal catalyst through a domino process that comprises the formation of a Csp3 -C and a Csp3 -N bond of the former hydrazonic carbon. The scope of the reaction has been explored by the preparation of over 50 examples of NH-unprotected spirocyclic derivatives. Importantly, this methodology could be applied for the preparation of alkaloid steroids from steroid N-tosylhydrazones.
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The 10-23 DNAzyme is an artificially developed Mg2+ -dependent catalytic oligonucleotide that can cleave an RNA substrate in a sequence-specific fashion. In this study, new split 10-23 DNAzymes made of two nonfunctional fragments, one of which carries a boronic acid group at its 5' end, while the other has a ribonucleotide at its 3' end, were designed. Herein it is demonstrated that the addition of Mg2+ ions leads to assembly of the fragments, which in turn induces the formation of a new boronate internucleoside linkage that restores the DNAzyme activity. A systematic evaluation identified the best-performing system. The results highlight key features for efficient control of DNAzyme activity through the formation of boronate linkages.