Showing papers on "Copper-free click chemistry published in 2011"

From mechanism to mouse: a tale of two bioorthogonal reactions.

Abstract: Bioorthogonal reactions are chemical reactions that neither interact with nor interfere with a biological system. The participating functional groups must be inert to biological moieties, must selectively reactive with each other under biocompatible conditions, and, for in vivo applications, must be nontoxic to cells and organisms. Additionally, it is helpful if one reactive group is small and therefore minimally perturbing of a biomolecule into which it has been introduced either chemically or biosynthetically. Examples from the past decade suggest that a promising strategy for bioorthogonal reaction development begins with an analysis of functional group and reactivity space outside those defined by Nature. Issues such as stability of reactants and products (particularly in water), kinetics, and unwanted side reactivity with biofunctionalities must be addressed, ideally guided by detailed mechanistic studies. Finally, the reaction must be tested in a variety of environments, escalating from aqueous medi...

Genetically encoded copper-free click chemistry.

Abstract: The ability to visualize biomolecules within living specimen by engineered fluorescence tags has become a major tool in modern biotechnology and cell biology. Encoding fusion proteins with comparatively large fluorescent proteins (FPs) as originally developed by the Chalfie and Tsien groups is currently the most widely applied technique.[1] As synthetic dyes typically offer better photophysical properties than FPs, alternative strategies have been developed based on genetically encoding unique tags such as Halo and SNAP tags, which offer high specificity but are still fairly large.[2] Small tags like multi-histidine[3] or multi-cysteine motifs[4] may be used to recognize smaller fluorophores, but within the cellular environment they frequently suffer from poor specificity as their basic recognition element is built from native amino acid side chains. Such drawbacks may be overcome by utilizing bioorthogonal chemistry that relies on coupling exogenous moieties of non-biological origin under mild physiological conditions. A powerful chemistry that fulfils these requirements is the Huisgen type (3+2) cycloaddition between azides and alkynes (a form of click chemistry[5]). By utilizing supplementation-based incorporation techniques and click reactions Beatty et al. coupled azide derivatized dyes to Escherichia coli expressing proteins bearing linear alkynes.[6] However, this azide–alkyne cycloaddition required copper(I) as a catalyst (CuAAC), which strongly reduces biocompatibility (but see Ref. [7]). This limitation has been overcome by Bertozzi and co-workers, who showed that the “click” reaction readily proceeds when utilizing ring-strained alkynes as a substrate[8] and since then this strain-promoted azide–alkyne cycloaddition (SPAAC) has found increasing applications in labeling, for example, carbohydrates,[9] nucleotides,[10] and lipids.[11] Further expanding the potential of this approach, Ting and co-workers engineered a lipolic acid ligase which ligates a small genetically encoded recognition peptide to a cylcooctyne-containing substrate. In a second step the incorporated cyclooctyne moiety then functioned as a specific site for labeling in cells.[12]

Copper-Free Click for PET: Rapid 1,3-Dipolar Cycloadditions with a Fluorine-18 Cyclooctyne.

Abstract: The strain-promoted click 1,3-dipolar cycloaddition reactions involving azides and cyclooctynes for the synthesis of triazoles offer the advantage of being able to be performed in biological settings via copper-free chemistries. While strained reagents conjugated to optical dyes and radiometal conjugates have been reported, cyclooctyne reagents labeled with fluorine-18 (18F) and radiochemically evaluated in a copper-free click reaction have yet to be explored. This report describes the conversion of a bifunctional azadibenzocyclooctyne (ADIBO) amine to the 18F-labeled cyclooctyne 4, the subsequent fast copper-free 1,3-dipolar cycloaddition reaction with alkyl azides at 37 °C (>70% radiochemical conversion in 30 min), and biological evaluations (serum stability of >95% at 2 h). These findings demonstrate the excellent reactivity of the 18F-labeled cyclooctyne 4 with readily available azides that will allow future work focusing on rapid copper-free in vitro and in vivo click chemistries for PET imaging usin...

Surface modification of silicon nanowires via copper-free click chemistry.

Abstract: A two-step process based on copper-free click chemistry is described, by which the surface of silicon nanowires can be functionalized with specific organic substituents. A hydrogen-terminated nanowire surface is first primed with a monolayer of an α,ω-diyne and thereby turned into an alkyne-terminated, clickable platform, which is subsequently coupled with an overlayer of an organic azide carrying the desired terminal functionality. The reactive, electron-deficient character of the employed diyne enabled a quantitative coupling reaction at 50 °C without metal catalysis, which opens up a simple and versatile route for surface functionalization under mild conditions without any potentially harmful additives.

In vivo copper-free click chemistry for delivery of therapeutic and/or diagnostic agents

Abstract: The present application discloses compositions and methods of synthesis and use involving click chemistry reactions for in vivo or in vitro formation of therapeutic and/or diagnostic complexes. Preferably, the diagnostic complex is of use for 18F imaging, while the therapeutic complex is of use for targeted delivery of chemotherapeutic drugs or toxins. More preferably, a chelating moiety or targetable construct may be conjugated to a targeting molecule, such as an antibody or antibody fragment, using a click chemistry reaction involving cyclooctyne, nitrone or azide reactive moieties. In most preferred embodiments, the click chemistry reaction occurs in vivo. In vivo click chemistry is not limited to 18F labeling but can be used for delivering a variety of therapeutic and/or diagnostic agents.

A Mild, Large‐Scale Synthesis of 1,3‐Cyclooctanedione: Expanding Access to Difluorinated Cyclooctyne for Copper‐Free Click Chemistry.

Abstract: We report the large-scale synthesis of 1,3-cyclooctanedione in five steps with 29% yield. This molecule is a synthetic precursor to difluorinated cyclooctyne, which participates in a bioorthogonal copper-free click reaction with azides. The final step demonstrates the first successful application of the Wacker–Tsuji oxidation to form a cyclic 1,3-dione.