4277-34-3Relevant academic research and scientific papers
General, Divergent Platform for Diastereoselective Synthesis of trans-Cyclooctenes with High Reactivity and Favorable Physiochemical Properties**
Pigga, Jessica E.,Rosenberger, Julia E.,Jemas, Andrew,Boyd, Samantha J.,Dmitrenko, Olga,Xie, Yixin,Fox, Joseph M.
supporting information, p. 14975 - 14980 (2021/05/31)
trans-Cyclooctenes (TCOs) are essential partners in the fastest known bioorthogonal reactions, but current synthetic methods are limited by poor diastereoselectivity. Especially hard to access are hydrophilic TCOs with favorable physicochemical properties for live cell or in vivo experiments. Described is a new class of TCOs, “a-TCOs”, prepared in high yield by stereocontrolled 1,2-additions of nucleophiles to trans-cyclooct-4-enone, which itself was prepared on a large scale in two steps from 1,5-cyclooctadiene. Computational transition-state models rationalize the diastereoselectivity of 1,2-additions to deliver a-TCO products, which were also shown to be more reactive than standard TCOs and less hydrophobic than even a trans-oxocene analogue. Illustrating the favorable physicochemical properties of a-TCOs, a fluorescent TAMRA derivative in live HeLa cells was shown to be cell-permeable through intracellular Diels–Alder chemistry and to wash out more rapidly than other TCOs.
A Simple, Readily Accessible, and Effective Apparatus for the Photoisomerization of cis -Cyclooctenes to trans -Cyclooctenes
Pickel, Thomas C.,Genung, Nathan E.,Guckian, Kevin M.,Shi, Xianglin
supporting information, p. 1711 - 1713 (2021/08/10)
A simple, cost effective, and readily accessible apparatus for the photoisomerization of cis -cyclooctenes to trans -cyclooctenes is described. Utilizing only FEP tubing, aluminum vent pipe, a household germicidal lamp, and a flash chromatography system, trans -cyclooctenes can be prepared in good yield.
A Bioorthogonal Click Chemistry Toolbox for Targeted Synthesis of Branched and Well-Defined Protein–Protein Conjugates
Baalmann, Mathis,Bitsch, Sebastian,Deweid, Lukas,Ilkenhans, Nadja,Kolmar, Harald,Neises, Laura,Schneider, Hendrik,Werther, Philipp,Wilhelm, Jonas,Wolfring, Martin,Wombacher, Richard,Ziegler, Michael J.
, p. 12885 - 12893 (2020/06/02)
Bioorthogonal chemistry holds great potential to generate difficult-to-access protein–protein conjugate architectures. Current applications are hampered by challenging protein expression systems, slow conjugation chemistry, use of undesirable catalysts, or often do not result in quantitative product formation. Here we present a highly efficient technology for protein functionalization with commonly used bioorthogonal motifs for Diels–Alder cycloaddition with inverse electron demand (DAinv). With the aim of precisely generating branched protein chimeras, we systematically assessed the reactivity, stability and side product formation of various bioorthogonal chemistries directly at the protein level. We demonstrate the efficiency and versatility of our conjugation platform using different functional proteins and the therapeutic antibody trastuzumab. This technology enables fast and routine access to tailored and hitherto inaccessible protein chimeras useful for a variety of scientific disciplines. We expect our work to substantially enhance antibody applications such as immunodetection and protein toxin-based targeted cancer therapies.
Optimization of IEDDA bioorthogonal system: Efficient process to improve trans-cyclooctene/tetrazine interaction
Béquignat, Jean-Baptiste,Boucheix, Claude,Canitrot, Damien,Chezal, Jean-Michel,Degoul, Fran?oise,Miot-Noirault, Elisabeth,Moreau, Emmanuel,Navarro-Teulon, Isabelle,Quintana, Mercedes,Rondon, Aurélie,Taiariol, Ludivine,Ty, Nancy
supporting information, (2020/07/21)
The antibody pretargeting approach for radioimmunotherapy (RIT) using inverse electron demand Diels-Alder cycloaddition (IEDDA) constitutes an emerging theranostic approach for solid cancers. However, IEDDA pretargeting has not reached clinical trial. The major limitation of the IEDDA strategy depends largely on trans-cyclooctene (TCO) stability. Indeed, TCO may isomerize into the more stable but unreactive cis-cyclooctene (CCO), leading to a drastic decrease of IEDDA efficiency. We have thus developed both efficient and reproducible synthetic pathways and analytical follow up for (PEGylated) TCO derivatives, providing high TCO isomeric purity for antibody modification. We have set up an original process to limit the isomerization of TCO to CCO before the mAbs’ functionalization to allow high TCO/tetrazine cycloaddition.
COMPOSITIONS AND METHODS FOR DELIVERING A SUBSTANCE TO A BIOLOGICAL TARGET
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Paragraph 0106; 0107, (2020/03/26)
The present application provides compositions and methods using bioorthogonal inverse electron demand Diels-Alder cycloaddition reaction for rapid and specific covalent delivery of a payload to a ligand bound to a biological target.
Alkene–Azide 1,3-Dipolar Cycloaddition as a Trigger for Ultrashort Peptide Hydrogel Dissolution
Dadhwal, Sumit,Fairhall, Jessica M.,Goswami, Shailesh K.,Hook, Sarah,Gamble, Allan B.
supporting information, p. 1143 - 1150 (2018/11/23)
An alkene–azide 1,3-dipolar cycloaddition between trans-cyclooctene (TCO) and an azide-capped hydrogel that promotes rapid gel dissolution is reported. Using an ultrashort aryl azide-capped peptide hydrogel (PhePhe), we have demonstrated proof-of-concept where upon reaction with TCO, the hydrogel undergoes a gel–sol transition via 1,2,3-triazoline degradation and 1,6-self-immolation of the generated aniline. The potential application of this as a general trigger in sustained drug delivery is demonstrated through release of encapsulated cargo (doxorubicin). Administration of TCO resulted in 87 % of the cargo being released in 10 h, compared to 13–14 % in the control gels. This is the first example of a potential bioorthogonal-triggered hydrogel dissolution using a traditional click-type reaction. This type of stimulus could be extended to other aryl azide-capped hydrogels.
Site-Specific Antibody Functionalization Using Tetrazine-Styrene Cycloaddition
Umlauf, Benjamin J.,Mix, Kalie A.,Grosskopf, Vanessa A.,Raines, Ronald T.,Shusta, Eric V.
, p. 1605 - 1613 (2018/05/14)
Biologics, such as antibody-drug conjugates, are becoming mainstream therapeutics. Consequently, methods to functionalize biologics without disrupting their native properties are essential for identifying, characterizing, and translating candidate biologics from the bench to clinical practice. Here, we present a method for site-specific, carboxy-terminal modification of single-chain antibody fragments (scFvs). ScFvs displayed on the surface of yeast were isolated and functionalized by combining intein-mediated expressed protein ligation (EPL) with inverse electron-demand Diels-Alder (IEDDA) cycloaddition using a styrene-tetrazine pair. The high thiol concentration required to trigger EPL can hinder the subsequent chemoselective ligation reactions; therefore, the EPL reaction was used to append styrene to the scFv, limiting tetrazine exposure to damaging thiols. Subsequently, the styrene-functionalized scFv was reacted with tetrazine-conjugated compounds in an IEDDA cycloaddition to generate functionalized scFvs that retain their native binding activity. Rapid functionalization of yeast surface-derived scFv in a site-directed manner could find utility in many downstream laboratory and preclinical applications.
New multiblock copolymers of norbornene and 5-hydroxycyclooctene
Denisova, Yulia I.,Gringolts, Maria L.,Roenko, Alexei V.,Shandryuk, Georgiy A.,Finkelshtein, Eugene Sh.,Kudryavtsev, Yaroslav V.
, p. 416 - 418 (2017/08/02)
Cross-metathesis of 5-hydroxycyclooctene and norbornene homopolymers affords the multiblock copolymer possessing a broad range in the degree of blockiness (from 0.03 to 1).
Novel Super-Resolution Imaging Compositions and Methods Using Same
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, (2016/05/24)
The invention provides compositions that may be used for imaging intracellular structures. The invention further provides methods of imaging intracellular structures. In certain embodiments, the compositions of the invention include trans-cyclooctene-containing ceramide lipids and tetrazine-containing rhodamine-related dyes.
Efficient low-cost preparation of trans-cyclooctenes using a simplified flow setup for photoisomerization
Svatunek, Dennis,Denk, Christoph,Rosecker, Veronika,Sohr, Barbara,Hametner, Christian,Allmaier, Günter,Fr?hlich, Johannes,Mikula, Hannes
, p. 579 - 585 (2016/03/19)
Bioorthogonal ligations have emerged as highly versatile chemical tools for biomedical research. The exceptionally fast reaction between 1,2,4,5-tetrazines and trans-cyclooctenes (TCOs), also known as tetrazine ligation, is frequently used in this regard. Growing numbers of applications for the tetrazine ligation led to an increased demand for TCO compounds, whose commercial availability is still very limited. Reported photochemical procedures for the preparation of TCOs using flow chemistry are straightforward and high yielding but require expensive equipment. Within this contribution, we present the construction and characterization of a low-cost flow photoreactor assembled from readily accessible components. Syntheses of all commonly used trans-cyclooctene derivatives were successfully carried out using the described system. We are convinced that the presented system for photoisomerization will promote access to bioorthogonally reactive TCO derivatives.
