Synthetic Strategies for the Biotinylation of Bioactive Small Molecules

Trippier, Paul C.

doi:10.1002/cmdc.201200498

Cited by 35 publications

(15 citation statements)

References 105 publications

(147 reference statements)

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“…In a second step the bioorthogonal reporter reacts with a molecule of interest bearing a complementary reactive handle. This approach has been used to install a diverse array of molecules for (i) fluorescent labelling, 8 (ii) glycosylation, 10 (iii) lipidation, 11 (iv) ubiquitination, 12 (v) PEGylation, 13 (vi) biotinylation, 14 and (vii) drugs. 15 This journal is © The Royal Society of Chemistry 2017…”

Section: Introductionmentioning

confidence: 99%

Inverse electron demand Diels–Alder reactions in chemical biology

2017

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The emerging inverse electron demand Diels-Alder (IEDDA) reaction stands out from other bioorthogonal reactions by virtue of its unmatchable kinetics, excellent orthogonality and biocompatibility. With the recent discovery of novel dienophiles and optimal tetrazine coupling partners, attention has now been turned to the use of IEDDA approaches in basic biology, imaging and therapeutics. Here we review this bioorthogonal reaction and its promising applications for live cell and animal studies. We first discuss the key factors that contribute to the fast IEDDA kinetics and describe the most recent advances in the synthesis of tetrazine and dienophile coupling partners. Both coupling partners have been incorporated into proteins for tracking and imaging by use of fluorogenic tetrazines that become strongly fluorescent upon reaction. Selected notable examples of such applications are presented. The exceptional fast kinetics of this catalyst-free reaction, even using low concentrations of coupling partners, make it amenable for in vivo radiolabelling using pretargeting methodologies, which are also discussed. Finally, IEDDA reactions have recently found use in bioorthogonal decaging to activate proteins or drugs in gain-of-function strategies. We conclude by showing applications of the IEDDA reaction in the construction of biomaterials that are used for drug delivery and multimodal imaging, among others. The use and utility of the IEDDA reaction is interdisciplinary and promises to revolutionize chemical biology, radiochemistry and materials science.

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Section: Introductionmentioning

confidence: 99%

Inverse electron demand Diels–Alder reactions in chemical biology

2017

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“…These reactions illustrate how azidation and cycloaddition can create bioconjugation methods for visualization and identification of cellular targets of biologically active natural products. 30 …”

mentioning

confidence: 99%

Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization

Sharma

Hartwig

2015

Nature

399

203

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Some enzymes are able to selectively oxidize unactivated aliphatic C-H bonds to form alcohols; however biological systems do not possess enzymes that are able to catalyze the analogous amination of a C-H bond.1,2 The absence of such chemistry is limiting because nitrogen-containing groups are found in therapeutic agents and clinically useful natural products. In one prominent example, the conversion of the ketone of erythromycin to the –N(Me)CH2– group in azithromycin leads to a compound that can be dosed once daily with a shorter length of treatment.3,4 For such reasons, synthetic chemists are very interested in identifying catalysts that can directly convert C-H bonds to C-N bonds. Most currently used catalysts for C-H bond amination are ill suited for the functionalization of complex molecules, because they require excess substrate or directing groups, harsh reaction conditions, weak or acidic C-H bonds, or reagents containing specialized groups on the nitrogen atom.5-14 Among C-H bond amination reactions, those forming a carbon-nitrogen bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to generate enzymatically from ketone or alcohol precursors.15 In this manuscript, we report a mild, selective, iron-catalyzed azidation of tertiary C-H bonds with substrate as limiting reagent. The reaction tolerates aqueous environments and is suitable for “late-stage” functionalization of complex structures. Moreover, this azidation creates the ability to install a range of nitrogen functional groups, including those from bio-orthogonal Huisgen “click” cycloadditions and the Staudinger ligation.16-19 For these reasons, we anticipate this methodology will create opportunities to easily modify natural products, their precursors, and their derivatives to analogs that contain distinct polarity and charge from nitrogen-containing groups. It could also be used to help identify targets of biologically active molecules by creating a point of attachment, for example to fluorescent tags or ‘handles’ for affinity chromatography, directly onto complex molecular structures.

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“…The appendage of a biotin moiety to a bioactive probe offers the opportunity to elucidate and analyze intracellular binding partners of the probe. Biotinylation profits from the exceedingly strong interaction between biotin and either avidin or streptavidin (Trippier, 2013;Verdoes and Verhelst, 2016;Chakrabarty et al, 2019). Accordingly, in order to provide tool compounds to unravel hitherto unknown processes of inflammasome activation and dynamics, we designed NLRP3-specific probes with either coumarin 343 or biotin.…”

Section: Resultsmentioning

confidence: 99%

Development of Fluorescent and Biotin Probes Targeting NLRP3

et al. 2021

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Extracellular signals drive the nucleation of the NLRP3 inflammasome which leads to the release of cytokines and causes inflammatory events. Hence, the inflammasome has gained enormous momentum in biomedical basic research. The detailed mechanisms of inflammasome generation and regulation remain to be elucidated. Our study was directed toward the design, convergent synthesis, and initial biochemical evaluation of activity-based probes addressing NLRP3. For this purpose, probes were assembled from a CRID3/MCC950-related NLRP3-binding unit, a linker portion and a coumarin 343 fluorophore or biotin. The affinity of our probes to NLRP3 was demonstrated through SPR measurements and their cellular activity was confirmed by reduction of the interleukin 1β release from stimulated bone marrow-derived macrophages. The initial characterizations of NLRP3-targeting probes highlighted the coumarin probe 2 as a suitable tool compound for the cellular and biochemical analysis of the NLRP3 inflammasome.

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Synthetic Strategies for the Biotinylation of Bioactive Small Molecules

Cited by 35 publications

References 105 publications

Inverse electron demand Diels–Alder reactions in chemical biology

Inverse electron demand Diels–Alder reactions in chemical biology

Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization

Development of Fluorescent and Biotin Probes Targeting NLRP3

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