Showing papers in "Organic and Biomolecular Chemistry in 2008"
TL;DR: The present article aims to help researchers enter this exciting research field, and to highlight recent advances in the design of G-quadruplex ligands.
Abstract: Over the past decade, nucleic acid chemists have seen the spectacular emergence of molecules designed to interact efficiently and selectively with a peculiar DNA structure named G-quadruplex. Initially derived from classical DNA intercalators, these G-quadruplex ligands progressively became the focal point of new excitement since they appear to inhibit selectively the growth of cancer cells thereby opening interesting perspectives towards the development of novel anti-cancer drugs. The present article aims to help researchers enter this exciting research field, and to highlight recent advances in the design of G-quadruplex ligands.
681 citations
TL;DR: The concept of "frustrated Lewis pairs" is described and shown to result in molecular systems capable of unique reactivity as well as applications in catalysis.
Abstract: The concept of “frustrated Lewis pairs” is described and shown to result in molecular systems capable of unique reactivity as well as applications in catalysis.
534 citations
TL;DR: These powerful synthetic methodologies serve as efficient approaches to the construction of complex chiral molecular architectures from simple achiral materials in one-pot transformations under mild conditions with high stereocontrol.
Abstract: The utilisation of chiral secondary amines as promoters for asymmetric cascade reactions has been subject of intensive research in asymmetric organocatalysis in the past few years. Key developments in this area are highlighted in this review. As shown, these powerful synthetic methodologies serve as efficient approaches to the construction of complex chiral molecular architectures from simple achiral materials in one-pot transformations under mild conditions with high stereocontrol.
446 citations
TL;DR: This review highlights achievements in cell-penetrating peptides and illustrates the numerous examples where peptide chemistry was exploited as a means to provide new tools for biology and medicine.
Abstract: Cell-penetrating peptides (CPPs) have found numerous applications in biology and medicine since the first synthetic cell-permeable sequence was identified two decades ago. Numerous types of drugs have been transported into cells using CPPs, including small-molecule pharmaceuticals, therapeutic proteins, and antisense oligonucleotides. Improved agents for medical imaging have been generated by conjugation with CPPs, with the appended peptides promoting cellular uptake and in some cases, cell-type specificity. Organelle-specific CPPs have also been generated, providing a means to target specific subcellular sites. This review highlights achievements in this area and illustrates the numerous examples where peptide chemistry was exploited as a means to provide new tools for biology and medicine.
405 citations
TL;DR: This emerging area examines recent developments of palladium-catalyzed difunctionalization reactions, with a focus on mechanistic strategies that allow for functionalization of a common palladium alkyl intermediate.
Abstract: Alkene difunctionalization, the addition of two functional groups across a double bond, exemplifies a class of reactions with significant synthetic potential. This emerging area examines recent developments of palladium-catalyzed difunctionalization reactions, with a focus on mechanistic strategies that allow for functionalization of a common palladium alkyl intermediate.
349 citations
TL;DR: Fungi treated with DNA methyltransferase and histone deacetylase inhibitors exhibited natural product profiles with enhanced chemical diversity demonstrating that small-molecule epigenetic modifiers are effective tools for rationally controlling the native expression of fungal biosynthetic pathways and generating new biomolecules.
Abstract: Fungi treated with DNA methyltransferase and histone deacetylase inhibitors exhibited natural product profiles with enhanced chemical diversity demonstrating that small-molecule epigenetic modifiers are effective tools for rationally controlling the native expression of fungal biosynthetic pathways and generating new biomolecules.
305 citations
TL;DR: Enamides display a fine balance of stability and reactivity, which is now leading to their increasing use in organic synthesis, and recent examples of these compounds as substrates are discussed in this article.
Abstract: Enamides display a fine balance of stability and reactivity, which is now leading to their increasing use in organic synthesis. Enamides offer multiple opportunities for the inclusion of nitrogen based functionality into organic systems. Recent examples of these compounds as substrates are discussed in this article.
263 citations
TL;DR: Diversity-oriented synthesis, which aims to prepare efficiently collections of skeletally diverse small molecules, has developed in the synthetic approaches it employs and three general strategies are described.
Abstract: Since our emerging area article, diversity-oriented synthesis (DOS), which aims to prepare efficiently collections of skeletally diverse small molecules, has developed in the synthetic approaches it employs. This article describes three general strategies, highlighting some successful examples. The utility of DOS, in the interrogation of chemical space and in the identification of novel biologically active lead compounds, is also discussed.
251 citations
TL;DR: This short account discloses the recent results of inter- and intramolecular enantioselective cycloadditions of alkyne and/or alkene moiety using chiral transition metal catalysts.
Abstract: Enantioselective cycloaddition using chiral transition metal catalysts is an atom-economical and efficient synthetic tool for the construction of chiral carbo- and heterocyclic skeletons. This short account discloses our recent results of inter- and intramolecular enantioselective [2 + 2 + 2] cycloadditions of alkyne and/or alkene moiety(ies). Chiral iridium complexes catalyzed the alkyne trimerization for the generation of axial chirality(ies), and chiral rhodium ones catalyzed alkyne-alkyne-alkene cyclization for the generation of a quaternary carbon including spirocyclic system.
242 citations
TL;DR: The primary amino functions, rather than the secondary pyrrolidine moiety, have been shown to provide unique reactivity and stereoselectivity in asymmetric aldol and Mannich reactions.
Abstract: Despite the recent spectacular advances in asymmetric organocatalysis, proline and its analogues have been predominantly employed as organocatalysts in reactions utilizing enamine intermediates. Recent studies of enantioselective organocatalytic reactions promoted by primary amino acids and their derivatives are described in this account. The primary amino functions, rather than the secondary pyrrolidine moiety, have been shown to provide unique reactivity and stereoselectivity in asymmetric aldol and Mannich reactions.
237 citations
TL;DR: The applications of phthalocyanines, the possibility of preparing novel related porphyrinoids with different colour properties and, consequently, new emerging applications, are discussed.
Abstract: This paper examines the preparation of tailor-made azaporphyrins and analogues exhibiting their Q-bands in several particular and predetermined regions of the electromagnetic spectrum. The applications of phthalocyanines, the possibility of preparing novel related porphyrinoids with different colour properties and, consequently, new emerging applications, are discussed.
TL;DR: The most recent advances in the field of dynamic combinatorial chemistry that have been developed to overcome limitations and explore new areas of application are presented.
Abstract: Dynamic combinatorial chemistry makes use of reversible reactions between functionalised monomeric building blocks to generate a mixture of products (dimers or oligomers) under thermodynamic equilibrium. This system reorganises upon addition of a target so that species that bind to, and are therefore stabilised by the target, are favourably formed and are thus amplified. Since the mid-1990’s, dynamic combinatorial chemistry has been successfully applied to the identification/selection of ion receptors, enzyme inhibitors, catalysts, materials and nucleic acid ligands. Although it is now established as a powerful tool with broad applications some intrinsic limitations appeared when working on systems of increasing complexity. We present here the most recent advances in the field of dynamic combinatorial chemistry that have been developed to overcome these limitations and explore new areas of application.
TL;DR: N-Heterocyclic carbenes promote the formal [2+2] cycloaddition of ketenes with N-tosyl imines to give the corresponding beta-lactams in good to excellent isolated yields; chiral NHCs give beta-Lactam in high e.e. after crystallisation.
Abstract: N-Heterocyclic carbenes promote the formal [2+2] cycloaddition of ketenes with N-tosyl imines to give the corresponding β-lactams in good to excellent isolated yields; chiral NHCs give β-lactams in high e.e. after crystallisation.
TL;DR: This Perspective highlightsphiphilic molecules based on nucleosides, nucleotides and oligonucleotides, their synthesis, supramolecular organization as well as their applications in the field of biotechnology.
Abstract: Amphiphilic molecules based on nucleosides, nucleotides and oligonucleotides are finding more and more biotechnological applications. This Perspective highlights their synthesis, supramolecular organization as well as their applications in the field of biotechnology.
TL;DR: It is illustrated how the 'fluorophore-spacer-receptor' format of fluorescent PET (photoinduced electron transfer) sensors and switches can be logically extended in many different directions, and common sensing issues such as dynamic range, internal referencing, selectivity, mapping and space resolution are addressed.
Abstract: Using cartoons as an organizational aid, we illustrate how the ‘fluorophore–spacer–receptor’ format of fluorescent PET (photoinduced electron transfer) sensors and switches can be logically extended in many different directions. These include emissive sensors for various chemical species and properties, and exploit various kinds of emission. Common sensing issues such as dynamic range, internal referencing, selectivity, mapping and space resolution are addressed. The sensory output function is also developed into more complex forms, molecular logic/computation being one such example. Molecular logic leads to molecular arithmetic. Real-life applications to physiological monitoring, medical diagnostics and molecular computational identification of small objects are included.
TL;DR: Various metal complexes can serve as catalyst precursors for the catalytic addition of alkyne C-H, amine N- H, and phosphine P-H bonds to carbodiimides, to give a new family of propiolamidines, guanidines and phosphaguanidine, some of which were difficult to prepare previously.
Abstract: Various metal complexes (e.g., lanthanides, early transition metals, and alkali metals) can serve as catalyst precursors for the catalytic addition of alkyne C–H, amine N–H, and phosphine P–H bonds to carbodiimides, to give a new family of propiolamidines, guanidines, and phophaguanidines, some of which were difficult to prepare previously. The catalytic reaction proceeds generally through nucleophilic addition of an M–ER (E = CR1R2, NR1, PR1) bond, which is formed by an acid–base reaction between a catalyst precursor and a RE–H bond, to a carbodiimide compound, followed by protonolysis of the resultant amidinate–(phospha)guanidinate species “{R′NC(ER)NR′}M” with RE–H.
TL;DR: N-Myristoyl transferase-mediated labelling using a substrate modified with an azide or alkyne tag is described as an efficient and site-selective method for the introduction of a bioorthogonal tag at the N-terminus of a recombinant protein.
Abstract: N-Myristoyl transferase-mediated labelling using a substrate modified with an azide or alkyne tag is described as an efficient and site-selective method for the introduction of a bioorthogonal tag at the N-terminus of a recombinant protein. The procedure may be performed in vitro, or in a single over-expression/tagging step in vivo in bacteria; tagged proteins may then be captured using Staudinger-Bertozzi or 'click' chemistry protocols to introduce a secondary label for downstream analysis. The straightforward synthesis of the chemical and molecular biological tools described should enable their use in a wide range of N-terminal labelling applications.
TL;DR: Recent advances in protein imprinting shown here demonstrate the possibility of this technique as a future technology of protein recognition.
Abstract: This article gives the recent developments in molecular imprinting for proteins. Currently bio-macromolecules such as antibodies and enzymes are mainly employed for protein recognition purposes. However, such bio-macromolecules are sometimes difficult to find and/or produce, therefore, receptor-like synthetic materials such as protein-imprinted polymers have been intensively studied as substitutes for natural receptors. Recent advances in protein imprinting shown here demonstrate the possibility of this technique as a future technology of protein recognition.
TL;DR: An MCoTI analogue is reported that is a selective low-microM inhibitor of foot-and-mouth-disease virus (FMDV) 3C protease, the first reported peptide-based inhibitor of this important viral enzyme.
Abstract: The naturally-occurring cyclic cystine-knot microprotein trypsin inhibitors MCoTI-I and MCoTI-II have been synthesised using both thia-zip native chemical ligation and a biomimetic strategy featuring chemoenzymatic cyclisation by an immobilised protease. Engineered analogues have been produced containing a range of substitutions at the P1 position that redirect specificity towards alternative protease targets whilst retaining excellent to moderate affinity. Furthermore, we report an MCoTI analogue that is a selective low-microM inhibitor of foot-and-mouth-disease virus (FMDV) 3C protease, the first reported peptide-based inhibitor of this important viral enzyme.
TL;DR: This Perspective briefly reviews the structure and mechanism, physiological role, and upregulation and induction of the enzyme, but focuses on the synthesis of new heterocyclic quinones and their metabolism by recombinant human NQO1.
Abstract: The quinone reductase enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes the two-electron reduction of quinones. This Perspective briefly reviews the structure and mechanism, physiological role, and upregulation and induction of the enzyme, but focuses on the synthesis of new heterocyclic quinones and their metabolism by recombinant human NQO1. Thus a range of indolequinones, some of which are novel analogues of mitomycin C, benzimidazolequinones, benzothiazolequinones and quinolinequinones have been prepared and evaluated, leading to detailed knowledge of the structural requirements for efficient metabolism by the enzyme. Potent mechanism-based inhibitors (suicide substrates) of NQO1 have also been developed. These indolequinones irreversibly alkylate the protein, preventing its function both in standard enzyme assays and also in cells. Some of these quinones are also potent inhibitors of growth of human pancreatic cancer cells, suggesting a potential role for such compounds as therapeutic agents.
TL;DR: The nucleophilic nature of cyanides is used to create a simple, sensitive, and highly effective sensor, 2-(trifluoroacetylamino)anthraquinone (2-TFAQ), for the easy "naked-eye" detection of very low concentrations of cyanide in an aqueous environment.
Abstract: The nucleophilic nature of cyanide is used to create a simple, sensitive, and highly effective sensor, 2-(trifluoroacetylamino)anthraquinone (2-TFAQ), for the easy "naked-eye" detection of very low concentrations of cyanide in an aqueous environment.
TL;DR: The combination of cross-coupling of NTPs with polymerase incorporation gives an efficient and straightforward two-step synthesis of modified nucleic acids.
Abstract: Construction of functionalized nucleic acids (DNA or RNA) via polymerase incorporation of modified nucleoside triphosphates is reviewed and selected applications of the modified nucleic acids are highlighted. The classical multistep approach for the synthesis of modified NTPs by triphosphorylation of modified nucleosides is compared to the novel approach consisting of direct aqueous cross-coupling reactions of unprotected halogenated nucleoside triphosphates. The combination of cross-coupling of NTPs with polymerase incorporation gives an efficient and straightforward two-step synthesis of modified nucleic acids. Primer extension using biotinylated templates followed by separation using streptavidine-coated magnetic beads and DNA duplex denaturation is used for preparation of modified single stranded oligonucleotides. Examples of using this approach for electrochemical DNA labelling and bioanalytical applications are given.
TL;DR: The encapsulation and protection of glucose oxidase and horse radish peroxidase in PS-PIAT polymersomes is reported on and the demonstrated concept allows for further application in other enzymatic cascade reactions, bio-organic hybrid systems and biosensing devices.
Abstract: Polystyrene40-b-poly(isocyanoalanine(2-thiophen-3-yl-ethyl)amide)50 (PS-PIAT) polymersomes have the unique property of being sufficiently porous to allow diffusion of small (organic) substrates while retaining large biomolecules such as enzymes inside. Herein we report on the encapsulation and protection of glucose oxidase (GOx) and horse radish peroxidase (HRP) in PS-PIAT polymersomes and the successful employment of these functionalised nanoreactors in a cascade reaction. The demonstrated concept allows for further application in other enzymatic cascade reactions, bio-organic hybrid systems and biosensing devices.
TL;DR: A concise synthesis of phenanthridines via a microwave-assisted [2+2+3+2] cyclotrimerization reaction has been developed and is applicable to selective separation of Na6(CO3)(SO4)2, Na2CO3, and Na2SO4 from Na3SO4-based polymers.
Abstract: A concise synthesis of phenanthridines via a microwave-assisted [2+2+2] cyclotrimerization reaction has been developed.
TL;DR: The particular fluorous linker proved to maintain solubility of the growing oligosaccharide chain such that identical reaction solvent conditions and purification protocols could be used between glycosylation and deprotection reactions, thereby rendering the procedures amenable to automation.
Abstract: We report herein the first synthesis of linear and branched mannose oligosaccharides using fluorous-tag assistance with reagents and FSPE protocols that are amenable to automation. The particular fluorous linker proved to maintain solubility of the growing oligosaccharide chain such that identical reaction solvent conditions and purification protocols could be used between glycosylation and deprotection reactions, thereby rendering the procedures amenable to automation.
TL;DR: The Diels-Alder reaction between cyclopentadiene and three dienophiles having different hydrogen bond acceptor abilities has been carried out in several ionic liquids and molecular solvents in order to obtain information about the factors affecting reactivity and selectivity.
Abstract: The Diels–Alder reaction between cyclopentadiene and three dienophiles (acrolein, methyl acrylate and acrylonitrile) having different hydrogen bond acceptor abilities has been carried out in several ionic liquids and molecular solvents in order to obtain information about the factors affecting reactivity and selectivity. The solvent effects on these reactions are examined using multiparameter linear solvation energy relationships. The collected data provide evidence that the solvent effects are a function of both the solvent and the solute. For a solvent effect to be seen, the solute must have a complimentary character; selectivities and rates are determined by the solvent hydrogen bond donation ability (α) in the reactions of acrolein and methyl acrylate, but not of acrylonitrile.
TL;DR: Analysis of structural data and non-denturing mass spectrometric analyses led to the identification of broad spectrum inhibitors, including potent inhibitors of the CphA MBL (Aeromonas hydrophila), suggesting that the development of reasonably broad-spectrum MBL inhibitors should be possible.
Abstract: The development of broad-spectrum metallo-beta-lactamase (MBL) inhibitors is challenging due to structural diversity and differences in metal utilisation by these enzymes. Analysis of structural data, followed by non-denturing mass spectrometric analyses, identified thiols proposed to inhibit representative MBLs from all three sub-classes: B1, B2 and B3. Solution analyses led to the identification of broad spectrum inhibitors, including potent inhibitors of the CphA MBL (Aeromonas hydrophila). Structural studies revealed that, as observed for other B1 and B3 MBLs, inhibition of the L1 MBL thiols involves metal chelation. Evidence is reported that this is not the case for inhibition of the CphA enzyme by some thiols; the crystal structure of the CphA-Zn-inhibitor complex reveals a binding mode in which the thiol does not interact with the zinc. The structural data enabled the design and the production of further more potent inhibitors. Overall the results suggest that the development of reasonably broad-spectrum MBL inhibitors should be possible.
TL;DR: The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.
Abstract: The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.
TL;DR: In this review, the recent advances of PET using biomolecules, such as peptides, monoclonal antibodies, proteins, oligonucleotides, and glycoproteins will be described.
Abstract: Recently, PET has been paid a great deal of attention as a non-invasive imaging method. In this review, the recent advances of PET using biomolecules, such as peptides, monoclonal antibodies, proteins, oligonucleotides, and glycoproteins will be described. So far, PET of biomolecules has been mainly used for diagnosis of cancers. The biomolecules have been conjugated with the DOTA ligand, labeled with radiometals as the β+ emitter, and targeted to specific tumors, where they have enabled visualization of even small metastatic lesions, due to the high sensitivity of the PET scanners. Some of the biomolecules have been used not only for PET diagnosis, but also for radiotherapeutic treatments by simply changing the radiometals to β− emitters. Collaborative work between chemists, biologists, and physicians will be important for the future of biomolecule-based targeting and diagnosis.
TL;DR: The efficiency of oxidation was found to increase with the decrease in redox potential of the substrates, and the Marcus reorganisation energy for electron transfer to the T1 copper site was determined.
Abstract: Laccases catalyze the one-electron oxidation of a broad range of substrates coupled to the 4 electron reduction of O2 to H2O. Phenols are typical substrates, because their redox potentials (ranging from 0.5 to 1.0 V vs. NHE) are low enough to allow electron abstraction by the T1 Cu(II) that, although a relatively modest oxidant (in the 0.4–0.8 V range), is the electron-acceptor in laccases. The present study comparatively investigated the oxidation performances of Trametes villosa and Myceliophthora thermophila laccases, two enzymes markedly differing in redox potential (0.79 and 0.46 V). The oxidation efficiency and kinetic constants of laccase-catalyzed conversion of putative substrates were determined. Hammett plots related to the oxidation of substituted phenols by the two laccases, in combination with the kinetic isotope effect determination, confirmed a rate-determining electron transfer from the substrate to the enzyme. The efficiency of oxidation was found to increase with the decrease in redox potential of the substrates, and the Marcus reorganisation energy for electron transfer to the T1 copper site was determined. Steric hindrance to substrate docking was inferred because some of the phenols and anilines investigated, despite possessing a redox potential compatible with one-electron abstraction, were scarcely oxidised. A threshold value of steric hindrance of the substrate, allowed for fitting into the active site of T. villosa laccase, was extrapolated from structural information provided by X-ray analysis of T. versicolor lac3B, sharing an identity of 99% at the protein level, thus enabling us to assess the relative contribution of steric and redox properties of a substrate in determining its susceptibility to laccase oxidation. The inferred structural threshold is compatible with the distance between two phenylalanine residues that mark the entrance to the active site. Interaction of the substrate with other residues of the active site is commented on.