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Cycloadditions in Bioorthogonal Chemistry
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by Haoxing Wu, Neal K. Devaraj
Bioorthogonal reactions have been widely used over the last 10 years for imaging, detection, diagnostics, drug delivery, and biomaterials. Tetrazine reactions are a recently developed class of inverse electron-demand Diels–Alder reactions used in bioorthogonal applications. Given their rapid tunable reaction rate and highly fluorogenic properties, tetrazine bioorthogonal reactions have come to be considered highly attractive tools for elucidating biological functions and messages in vitro and in vivo. In this chapter, we present recent advances expanding the scope of precursor reactivity and we introduce new biomedical methodology based on bioorthogonal tetrazine chemistry. We specifically highlight novel applications for different kinds of biomolecules, including nucleic acid, protein, antibodies, lipids, glycans, and bioactive small molecules, in the areas of imaging, detection, and diagnostics. We also briefly present other recently developed inverse electron-demand Diels–Alder bioorthogonal reactions. Lastly, we consider future directions and potential roles that inverse electron-demand Diels–Alder reactions may play in the fields of bioorthogonal and biomedical chemistry.
by Jan Dommerholt, Floris P. J. T. Rutjes, Floris L. van Delft
A nearly forgotten reaction discovered more than 60 years ago—the cycloaddition of a cyclic alkyne and an organic azide, leading to an aromatic triazole—enjoys a remarkable popularity. Originally discovered out of pure chemical curiosity, and dusted off early this century as an efficient and clean bioconjugation tool, the usefulness of cyclooctyne–azide cycloaddition is now adopted in a wide range of fields of chemical science and beyond. Its ease of operation, broad solvent compatibility, 100 % atom efficiency, and the high stability of the resulting triazole product, just to name a few aspects, have catapulted this so-called strain-promoted azide–alkyne cycloaddition (SPAAC) right into the top-shelf of the toolbox of chemical biologists, material scientists, biotechnologists, medicinal chemists, and more. In this chapter, a brief historic overview of cycloalkynes is provided first, along with the main synthetic strategies to prepare cycloalkynes and their chemical reactivities. Core aspects of the strain-promoted reaction of cycloalkynes with azides are covered, as well as tools to achieve further reaction acceleration by means of modulation of cycloalkyne structure, nature of azide, and choice of solvent.
Ludwig-Maximilians University, Department of Chemistry
Thomas Carell began his academic training in chemistry at the Universities of Münster and Heidelberg. In 1993 he obtained his doctorate with Prof. H. A. Staab at the Max Planck Institute of Medical Research. After postdoctoral training with Prof. J. Rebek at MIT (Cambridge, USA) in 1993-1995, Thomas Carell moved to the ETH Zürich (Switzerland) to the group of Prof. F. Diederich to start independent research. He obtained his habilitation in 1999, and in 2000 he accepted a full professor position for Organic Chemistry at the Philipps-Universität in Marburg (Germany). In 2004 he moved to the Ludwig-Maximilians-Universität (LMU) in Munich (Germany) where he now heads a research group in chemical biology focused on analyzing the chemistry of epigenetic programming in DNA and RNA. Thomas Carell is a member of the German National Academy Leopoldina and of the Berlin-Brandenburgische Academy of Arts and Sciences. He is the recipient of the Cross of Merit from the Federal Republic of Germany.
Institute of Organic Chemistry and Biochemistry (IOCB), AS CR, v.v.i.
M. Vrabel graduated in 2004 in organic chemistry at the Slovak University of Technology in Bratislava under the supervision of Professor Ľ. Fišera. He obtained his PhD in 2008 at The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB, AV CR) in Prague working with Professor M. Hocek on the development of electrochemical DNA sensors. After postdoctoral studies with Professor T. Carell at Ludwig-Maximilians University in Munich he accepted in 2014 an independent position as Junior Group Leader at IOCB in Prague. His research interests encompass the use of bioconjugation reactions to study biological processes and the development of novel diagnostic and therapeutic tools.
"Bioorthogonal chemistry has emerged as a new powerful tool that facilitates the study of structure and function of biomolecules in their native environment. A wide variety of bioorthogonal reactions that can proceed selectively and efficiently under physiologically relevant conditions are now available. The common features of these chemical reactions include: fast kinetics, tolerance to aqueous environment, high selectivity and compatibility with naturally occurring functional groups. The design and development of new chemical transformations in this direction is an important step to meet the growing demands of chemical biology. This chapter aims to introduce the reader to the field by providing an overview on general principles and strategies used in bioorthogonal chemistry. Special emphasis is given to cycloaddition reactions, namely to 1,3-dipolar cycloadditions and Diels–Alder reactions, as chemical transformations that play a predominant role in modern bioconjugation chemistry. The recent advances have established these reactions as an invaluable tool in modern bioorthogonal chemistry. The key aspects of the methodology as well as future outlooks in the field are discussed." in Bioorthogonal Chemistry—Introduction and Overview by Thomas Carell and Milan Vrabel