Huisgen-based conjugation of water-soluble porphyrins to deprotected sugars: Towards mild strategies for the labelling of glycans

Fully deprotected alkynyl-functionalised mono- and oligosaccharides undergo CuAAC-based conjugation with water-soluble porphyrin azides in aqueous environments. The mild reaction conditions are fully compatible with the presence of labile glycosidic bonds. This approach provides an ideal strategy to conjugate tetrapyrroles to complex carbohydrates

Core-Clickable PEG-Branch-Azide Bivalent-Bottle-Brush Polymers by ROMP: Grafting-Through and Clicking-To

The combination of highly efficient polymerizations with modular "click" coupling reactions has enabled the synthesis of a wide variety of novel nanoscopic tructures. Here we demonstrate the facile synthesis of a new class of clickable, branched nanostructures, polyethylene glycol (PEG)-branch-azide bivalent-brush polymers, facilitated by "graft-through" ring-opening metathesis polymerization of a branched norbornene-PEG-chloride macromonomer followed by halide-azide exchange. The resulting bivalent-brush polymers possess azide groups at the core near a polynorbornene backbone with PEG chains extended into solution; the structure resembles a unimolecular micelle. We demonstrate copper-catalyzed azide-alkre cycloaddition (CuAAC) "click-to" coupling of a photocleavable doxorubicin (DOX)-alkyne derivative to the azide core. The CuAAC coupling was quantitative across a wide range of nanoscopic sizes (similar to 6-similar to 50 nrn); UV photolysis of the resulting DOX-loaded materials yielded free DOX that was therapeutically effective against human cancer cells

Surface Modification of Melt Extruded Poly(ε-caprolactone) Nanofibers: Toward a New Scalable Biomaterial Scaffold.

A photochemical modification of melt-extruded polymeric nanofibers is described. A bioorthogonal functional group is used to decorate fibers made exclusively from commodity polymers, covalently attach fluorophores and peptides, and direct cell growth. Our process begins by using a layered coextrusion method, where poly(ε-caprolactone) (PCL) nanofibers are incorporated within a macroscopic poly(ethylene oxide) (PEO) tape through a series of die multipliers within the extrusion line. The PEO layer is then removed with a water wash to yield rectangular PCL nanofibers with controlled cross-sectional dimensions. The fibers can be subsequently modified using photochemistry to yield a "clickable" handle for performing the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction on their surface. We have attached fluorophores, which exhibit dense surface coverage when using ligand-accelerated CuAAC reaction conditions. In addition, an RGD peptide motif was coupled to the surface of the fibers. Subsequent cell-based studies have shown that the RGD peptide is biologically accessible at the surface, leading to increased cellular adhesion and spreading versus PCL control surfaces. This functionalized coextruded fiber has the advantages of modularity and scalability, opening a potentially new avenue for biomaterials fabrication

Continual reproduction of self-assembling oligotriazole peptide nanomaterials.

Autocatalytic chemical reactions, whereby a molecule is able to catalyze its own formation from a set of precursors, mimic nature's ability to generate identical copies of relevant biomolecules, and are thought to have been crucial for the origin of life. While several molecular autocatalysts have been previously reported, coupling autocatalytic behavior to macromolecular self-assembly has been challenging. Here, we report a non-enzymatic and chemoselective methodology capable of autocatalytically producing triskelion peptides that self-associate into spherical bioinspired nanostructures. Serial transfer experiments demonstrate that oligotriazole autocatalysis successfully leads to continual self-assembly of three-dimensional nanospheres. Triskelion-based spherical architectures offer an opportunity to organize biomolecules and chemical reactions in unique, nanoscale compartments. The use of peptide-based autocatalysts that are capable of self-assembly represents a promising method for the development of self-synthesizing biomaterials, and may shed light on understanding life's chemical origins.Molecules that act as both autocatalysts and material precursors offer exciting prospects for self-synthesizing materials. Here, the authors design a triazole peptide that self-replicates and then self-assembles into nanostructures, coupling autocatalytic and assembly pathways to realize a reproducing supramolecular system

Isolation of bis(copper) key intermediates in Cu-catalyzed azide-alkyne "click reaction".

The copper-catalyzed 1,3-dipolar cycloaddition of an azide to a terminal alkyne (CuAAC) is one of the most popular chemical transformations, with applications ranging from material to life sciences. However, despite many mechanistic studies, direct observation of key components of the catalytic cycle is still missing. Initially, mononuclear species were thought to be the active catalysts, but later on, dinuclear complexes came to the front. We report the isolation of both a previously postulated π,σ-bis(copper) acetylide and a hitherto never-mentioned bis(metallated) triazole complex. We also demonstrate that although mono- and bis-copper complexes promote the CuAAC reaction, the dinuclear species are involved in the kinetically favored pathway

Folding of a donor–acceptor polyrotaxane by using noncovalent bonding interactions

Mechanically interlocked compounds, such as bistable catenanes and bistable rotaxanes, have been used to bring about actuation in nanoelectromechanical systems (NEMS) and molecular electronic devices (MEDs). The elaboration of the structural features of such rotaxanes into macromolecular materials might allow the utilization of molecular motion to impact their bulk properties. We report here the synthesis and characterization of polymers that contain π electron-donating 1,5-dioxynaphthalene (DNP) units encircled by cyclobis(paraquat-p-phenylene) (CBPQT4+), a π electron-accepting tetracationic cyclophane, synthesized by using the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The polyrotaxanes adopt a well defined “folded” secondary structure by virtue of the judicious design of two DNP-containing monomers with different binding affinities for CBPQT4+. This efficient approach to the preparation of polyrotaxanes, taken alongside the initial investigations of their chemical properties, sets the stage for the preparation of a previously undescribed class of macromolecular architectures

Regioselective and stoichiometrically controlled conjugation of photodynamic sensitizers to a HER2 targeting antibody fragment

The rapidly increasing interest in the synthesis of antibody–drug conjugates as powerful targeted anticancer agents demonstrates the growing appreciation of the power of antibodies and antibody fragments as highly selective targeting moieties. This targeting ability is of particular interest in the area of photodynamic therapy, as the applicability of current clinical photosensitizers is limited by their relatively poor accumulation in target tissue in comparison to healthy tissue. Although synthesis of porphyrin–antibody conjugates has been previously demonstrated, existing work in this area has been hindered by the limitations of conventional antibody conjugation methods. This work describes the attachment of azide-functionalized, water-soluble porphyrins to a tratuzumab Fab fragment via a novel conjugation methodology. This method allows for the synthesis of a homogeneous product without the loss of structural stability associated with conventional methods of disulfide modification. Biological evaluation of the synthesized conjugates demonstrates excellent selectivity for a HER2 positive cell line over the control, with no dark toxicity observed in either case

Revisiting the mechanism of the mono nuclear copper-catalyzed cycloaddition of azide and alkynes (CuAAC) by the topology of ....

Comunicación presentada y aceptada en el CHITEL2013, XXXIX International Conference THEORETICAL CHEMISTS OF LATIN EXPRESSION (XXXIX Congreso Internacional de Químicos de Expresión Latina).Se analiza el mecanismo de la reacción de cicloadición, catalizada por Cu(I), de azidas a alquinos (CuAAC), haciendo uso de métodos DFT y de herramientas de análisis de la densidad electrónica basadas en la topología de su laplaciana

Self-healing metallo-supramolecular hydrogel based on specific Ni2+ coordination interactions of poly(ethylene glycol) with bistriazole pyridine ligands in the main chain

In this study, a supramolecular hydrogel formed by incorporating the 2,6-bis(1,2,3-triazol-4-yl)-pyridine (btp) ligand in the backbone of a polymer prepared by copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) "click" polyaddition reaction of 2,6-diethynylpyridine and diazido-poly(ethylene glycol) is reported. The hydrogelation is selectively triggered by the addition of Ni2+ ions to aqueous copolymer solutions. The gelation and rheological properties could be tuned by the change of metal to ligand ratio and polymer concentration. Interestingly, the hydrogel exhibits a fast (within 2 min) and excellent repeatable autonomic healing capacity without external stimuli. This self-healing behavior may find potential applications for the repairing of metal coatings, in the future

Enzymatic transhalogenation of dendritic RGD peptide constructs with the fluorinase

We thank EPSRC and the Scottish Imaging Network (SINAPSE) for grants. DO’H thanks the Royal Society for a Wolfson Research Merit Award and ST is grateful to the John and Kathleen Watson Scholarship for financial support. We are grateful to Dr Catherine Botting and Dr Sally Shirran of the St Andrews Mass Spectrometry Service for MALDI-MS acquisitions. We also thank Dr Sally Pimlott of the University of Glasgow for the use of radiochemistry facilities. Open access via RSC Gold for Gold.Peer reviewedPublisher PD