Wednesday, October 24, 2012

Clicking 1,2,4,5-tetrazine and cyclooctynes with tunable reaction rates

Control and Design of Mutual Orthogonality in Bioorthogonal Cycloadditions
Yong Liang, Joel L. Mackey, Steven A. Lopez, Fang Liu, and K. N. Houk

The azide–dibenzocyclooctyne and trans-cyclooctene–tetrazine cycloadditions are both bioorthogonal and mutually orthogonal: trans-cyclooctene derivatives greatly prefer to react with tetrazines rather than azides, while dibenzocyclooctyne derivatives react with azides but not with tetrazines under physiological conditions. DFT calculations used to identify the origins of this extraordinary selectivity are reported, and design principles to guide discovery of new orthogonal cycloadditions are proposed. Two new bioorthogonal reagents, methylcyclopropene and 3,3,6,6-tetramethylthiacycloheptyne, are predicted to be mutually orthogonal in azide and tetrazine cycloadditions. 

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Synthesis and Photophysics of Fully π-Conjugated Heterobis-Functionalized Polymeric Molecular Wires via Suzuki Chain-Growth Polymerization


A fast and efficient in situ synthetic approach to obtain fully π-conjugated polymers with degrees of polymerization up to 23 and near quantitative (>95%) heterobis-functionalization were presented by this manuscript. The synthesis relies on the key advantages of controlled Suzuki chain-growth polymerization: control over molecular weight, narrow polydispersity, and ability to define polymer end groups. The first end group is introduced through the initiator metal complex tBu3PPd(X)Br, while the second end group is added by quenching of the chain-growth polymerization with the desired boronic esters. In all cases, polymers obtained at 50% conversion showed excellent end group fidelity and high purity following a simple workup procedure, as determined by MALDI-TOF, GPC, and 1H and 2D NMR. End group functionalization altered the optoelectronic properties of the bridge polymer. Building on a common fluorene backbone, and guided by DFT calculations, donor and acceptor end groups were introduced to create polymeric molecular wires exhibiting charge transfer and energy transfer as characterized by fluorescence, absorption, and transient absorption spectroscopy as well as by fluorescence lifetime measurements.

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In Situ SVVYGLR Peptide Conjugation into Injectable Gelatin-Poly(ethylene glycol)-Tyramine Hydrogel via Enzyme-Mediated Reaction for Enhancement of Endothelial Cell Activity and Neo-Vascularization

The authors make gelatin-PEG tyramine gels (GPT gels) that they functionalize with a SVVYGLR peptide. The SVVYGLR sequence, often found near an RGD sequence in different types of ECM, has been shown to improve adhesion, migration, and tube formation of endothelial cells. Crosslinking and bioconjugation of the peptide sequence is done using a horseradish-peroxide (HRP) mediated tyrosine radical dimerization. The authors then demonstrate that human umbilical endothelial cells have better attachment and proliferation on gels containing the SVVYGLR sequence than on gels containing just RGD. They also look at the vascularization of gels subcutaneously injected into rats.

Most interesting aspects of the paper are the enzyme-mediated cross-linking and the SVVYGLR peptide.

Complex Polycyclic Scaffolds by Metathesis Rearrangement of Himbert Arene/Allene Cycloadducts

Jonathan K. Lam,† Yvonne Schmidt,† and Christopher D. Vanderwal*

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In this paper, the authors report an interesting two-step route for conversion of various analogs of amide above to the corresponding tricyclic structures.  The two steps are (1) alkyne-allene isomerization/intramolecular Diels Alder cycloaddition and (2) ROM-RCM.

Two Dimensional Nanoarrays of Individual Protein Molecules

Lei Shen1, Adam Garland1, Yini Wang2, Zicheng Li1, Christopher W. Bielawski1,*, Athena Guo2,*, X.-Y. Zhu1,*
In this paper, the authors report a 2-D array of protein molecules attached to a substrate via Cu-click chemistry (protein-azides + susbtrate-alkynes).  The reason the proteins are regularly spaced is b/c the substrate is a diblock co-polymer composed of PS and PHEMA blocks.  These polymers self-assemble to form 1-nm wide hexagonal PS domains in a PHEMA matrix.  Incorporation of PS-alkynes into the PS block results in attachment points for protein-azides that are ~1nm apart -- thus only one protein can attach per block.
Below are a diagram of the idea and the data from AFM studies (substrate and substrate + proteins).  They also do XPS (N1s) and SPR studies confirming irreversible binding of proteins.

Probing the conductance superposition law in single-molecule circuits with parallel paths

H. Vazquez, R. Skouta, S. Schneebeli, M. Kamenetska, R. Breslow, L. Venkataraman & M.S. Hybertsen
This paper presents experimental evidence that a parallel circuit in molecular electronics setting does not obey the Kirchhoff Rule, which states that the conductance of a parallel circuit is a sum of the parallel parts.  In this case, quantum interference is held as the culprit, giving rise to higher conductance! (actual conductance ~ 1.5 x that predicted by Kirchhoff).  Measurements were done using STM-break junction experiments, as well as DFT. 

Electrografting of calix[4]arenediazonium salts to form versatile robust platforms for spatially controlled surface functionalization

Electrografting of calix[4]arenediazonium salts to form versatile robust platforms for spatially controlled surface functionalization

Alice Mattiuzzi, Ivan Jabin, Claire mangeney, Clément Roux, Olivia Reinaud, Luis Santos, Jean-François Bergamini, Philippe Hapiot & Corinne Lagrost

"Calix[4]tetra-diazonium cations generated in situ from the corresponding tetra-anilines were electrografted on gold and carbon substrates. The well-preorganized macrocyclic structure of the calix[4]arene molecules allows the formation of densely packed monolayers. Through adequate decoration of the small rim of the calixarenes, functional molecules can then be introduced on the immobilized calixarene subunits, paving the way for an accurate spatial control of the chemical composition of a surface at molecular level."  One cool experiment is determination of surface coverage by functionalizing the electrode with COOH terminated calixarenes and then coupling on Fc moieties and doing CV.

NIR-Responsive and Lectin-Binding Doxorubicin-Loaded Nanomedicine from Janus-Type Dendritic PAMAM Amphiphiles

The authors prepare Janus-type dendrimers that self-assemble into micelles. The hydrophilic side contains lactose moieties that promote cell binding and internalization. The hydrophobic side has diazonaphthoqinone groups that undergo a Wolff rearrangement upon near-IR radiation, making the group hydrophilic and promoting micelle disassembly. The micelles were loaded with Dox and shown to release Dox in a controlled fashion.

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Poly[(ethylene oxide)-co-(methylene ethylene oxide)]: A hydrolytically degradable poly(ethylene oxide) platform

Pontus Lundberg,Bongjae F. Lee, Sebastiaan A. van den Berg, Eric D. Pressly, Annabelle Lee, Craig J. Hawker, and Nathaniel A. Lynd

This group synthesizes a degradable PEG-based polymer by making a copolymer of ethylene oxide with epichlorohydrin followed by elimination of the halide to incorporate degradable ethylene methylene oxide copolymer with ethylene oxide. This polymer degrades as pH 5.0 at 37 C, but is relatively stable over 70 hours at pH 7.4 at 6 C.

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Thiol and pH dual-responsive dynamic covalent shell cross-linked micelles for triggered release of chemotherapeutic drugs

Polymer Chemistry