Bioorthogonal chemical reactions, those that do not interact or interfere with biology, have allowed for exploration of numerous biological processes were previously difficult to study. The reaction azides strained alkynes, such as cyclooctynes, readily forms a triazole product without the need toxic catalyst. Here we describe biarylazacyclooctynone (BARAC) has exceptional kinetics and whose synthesis is designed be both modular scalable. We employed BARAC live cell fluorescence imaging...

The 1,3-dipolar cycloaddition of cyclooctynes with azides, also called "copper-free click chemistry", is a bioorthogonal reaction widespread applications in biological discovery. kinetics this are paramount importance for studies dynamic processes, particularly living subjects. Here we performed systematic analysis the effects strain and electronics on reactivity azides through both experimental measurements computational using density functional theory (DFT) distortion/interaction...

Peptidoglycan (PG) is an essential component of the bacterial cell wall. Although experiments with organisms in vitro have yielded a wealth information on PG synthesis and maturation, it unclear how these studies translate to bacteria replicating within host cells. We report chemical approach for probing vivo via metabolic labeling bioorthogonal chemistry. A wide variety species incorporated azide alkyne-functionalized d-alanine into their walls, which we visualized by covalent reaction...

Mycobacteria, including the pathogen Mycobacterium tuberculosis, use non-mammalian disaccharide trehalose as a precursor for essential cell-wall glycolipids and other metabolites. Here we describe strategy exploiting metabolic pathways to label in mycobacteria with azide-modified (TreAz) analogues. Subsequent bioorthogonal ligation alkyne-functionalized probes enabled detection visualization of cell-surface glycolipids. Characterization fates four TreAz analogues revealed unique labeling...

Highly reactive cyclooctynes have been sought as substrates for Cu-free cycloaddition reactions with azides in biological systems. To elevate the reactivities of cyclooctynes, two strategies, LUMO lowering through propargylic fluorination and strain enhancement fused aryl rings, explored. Here we report facile synthesis a difluorobenzocyclooctyne (DIFBO) that combines these modifications. DIFBO was so it spontaneously trimerized to form asymmetric products characterized by X-ray...

Cyclooctyne-based probes that become fluorescent upon reaction with azides are important targets for real-time imaging of azide-labeled biomolecules. The concise synthesis a coumarin-conjugated cyclooctyne, coumBARAC, undergoes 10-fold enhancement in fluorescence quantum yield triazole formation organic is reported. design principles embodied coumBARAC establish platform generating fluorogenic cyclooctynes suited biological imaging.

Mosquito control methods are vital to curtail the spread of life-threatening illnesses, such as dengue fever, malaria, and yellow fever. Vector technologies must be selective minimize deleterious effects on our ecosystem. Successful that mosquito larva populations utilize uniquely high alkaline nature midgut. Here, we present novel protected triazabutadienes (pTBD) deprotected under basic conditions larval midgut, releasing an aryl diazonium ion (ADI) results in protein modification. The...

Blisteringly fast: The potent cytotoxic blistering agent pederin has been synthesized (see scheme). synthesis is diastereoselective and concise (just 12 steps for the longest linear sequence), features a formal hetero-Diels–Alder reaction of hindered diene, Mukaiyama–Michael to set two additional stereocenters, Curtius rearrangement stereospecifically introduce aminal functionality. Supporting information this article available on WWW under...

The complexes Pd(diphos)(o-An)(I) (o-An = o-MeOC6H4; diphos dppe (3), (S,S)-Chiraphos (4), (R,R)-Me-Duphos (5), (R,S)-t-Bu-Josiphos (6), (R)-Tol-Binap (7)) were prepared. Complex 6 catalyzed the coupling of PH(Me)(Ph)(BH3) (2) with o-AnI in presence base to yield PAMP−BH3 (P(Me)(Ph)(o-An)(BH3) (1)) low enantiomeric excess. course stoichiometric reactions 3−7 2 and NaOSiMe3 depended on diphosphine ligand. Complexes 7 gave (1) Pd(0) species; no intermediates observed. With 3, intermediate...

Abstract Triazabutadienes are an understudied structural motif that have remarkable reactivity once rendered water‐soluble. It is shown these molecules readily release diazonium species in a pH‐dependent manner series of buffer solutions with pH ranges similar to those found cells. Upon further development, we expect this process will be well suited cargo‐release strategies and organelle‐specific bioconjugation reactions. These compounds offer one the mildest ways generating aqueous solutions.

Chemical modification of proteins has been crucial in engineering protein-based therapies, targeted biopharmaceutics, molecular probes, and biomaterials. Here, we explore the use a conjugation-based approach to sense alternative conformational states proteins. Tyrosine both hydrophobic hydrophilic qualities, thus allowing it be positioned at protein surfaces, or binding interfaces, buried within protein. can conjugated with 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione (PTAD). We hypothesized...

Controlling chemical reactivity using light is a longstanding practice within organic chemistry, yet little has been done to modulate the basicity of compounds. Reported herein triazabutadiene that rendered basic upon photoisomerization. The pH an aqueous solution containing water-soluble can be adjusted with 350 nm light. Upon synthesizing soluble in aprotic solvents, we noted similar light-induced change basicity. As proof concept took this photobase and used it catalyze condensation reaction.

Mycalamide B (MycB) is a marine sponge-derived natural product with potent antitumor activity. Although it has been shown to inhibit protein synthesis, the molecular mechanism of action by MycB remains incompletely understood. We verified inhibition translation elongation in vitro HCV IRES dual luciferase assays, ribosome assembly, and vivo [(35)S]methinione labeling experiments. Similar cycloheximide (CHX), inhibits through blockade eEF2-mediated translocation without affecting...

Triazabutadienes can be used to readily generate reactive aryl diazonium ions under mild, physiologically relevant conditions. These conditions are compatible with a range of functionalities that do not tolerate traditional ion generation. To increase the utility this releasing chemistry an alkyne-containing triazabutadiene was synthesized. The copper-catalyzed azide–alkyne cycloaddition ("Cu-click") reaction utilized modify and shown nitrogen-rich triazabutadiene. One triazole products...

Superschnell: Die Synthese des hochwirksamen cytotoxischen Wirkstoffs Pederin (siehe Schema) ist diastereoselektiv und kompakt (nur 12 Stufen für die längste lineare Sequenz) umfasst eine formale Hetero-Diels-Alder-Reaktion eines gehinderten Diens, Mukaiyama-Michael-Reaktion zur Erzeugung zweier zusätzlicher Stereozentren Curtius-Umlagerung, um Aminal-Funktion stereospezifisch einzuführen. Supporting information for this article is available on the WWW under...

A triarylphosphine reagent that reacts with organic azides to install amide-linked diazirines is reported. This traceless Staudinger complex yield diazirines, thus expanding the scope of utility both azide and diazirine chemistry.

Acetyl cyanide is utilized to synthesize fluorescent indolizines, benzo[<italic>d</italic>]pyrrolo[2,1-<italic>b</italic>]thiazoles, and pyrrolo[1,2-<italic>a</italic>]pyrazines in a single step.

Abstract The use of small‐molecule fluorophores to label proteins with minimal perturbation in response an external stimulus is a powerful tool probe chemical and biochemical environments. Herein, we describe the coumarin‐modified triazabutadiene that can deliver aryl diazonium ions fluorescently by tyrosine‐selective modification. labeling be triggered low‐pH‐induced liberation species, thus making fluorophore especially useful surroundings such as those found within late endosome....

Abstract Chemical crosslinking is a versatile tool for the examination of biochemical interactions, in particular host–pathogen interactions. We report critical first step toward goal probing these interactions by synthesis and use new heterobifunctional crosslinker containing triazabutadiene scaffold. The stable to protein conjugation liberates reactive aryl diazonium species upon irradiation with 350 nm light. highlight this technology modifying surface several proteins, including dengue...

This work describes the development of a highly stable and pH-responsive probe for lysine modification. The scaffold has marked stability in presence several biological nucleophiles across wide pH range (2–12). Several functional analogs showed robust labeling protein at > 9. Taken together, our system displays versatility can be easily adapted variety applications, while demonstrating suitable biologically compatible systems.

Restrain and release: A one-pot Mukaiyama–Michael/epoxidation sequence introduced three stereocenters, an intramolecular isocyanate trapping produced a rigid 10-membered cyclic carbamate, the selective opening of carbamate was used to reveal fully constructed natural product. Detailed facts importance specialist readers are published as ”Supporting Information”. Such documents peer-reviewed, but not copy-edited or typeset. They made available submitted by authors. Please note: The publisher...

Aryl diazonium ions have long been used in bioconjugation due to their reactivity toward electron-rich aryl residues, such as tyrosine. However, utility biological systems has restricted the requirement of harsh conditions for generation situ, well limited hydrolytic stability. Previous work describing a scaffold known triazabutadiene (TBD) shown ability protect allowing increased synthetic utility, triggered release under biologically relevant conditions. Herein, we describe synthesis and...

Abstract Recent work on triazabutadienes has shown that they have the ability to release aryl diazonium ions under exceptionally mild acidic conditions. There are instances require this be prevented or minimized. Accordingly, a base‐labile protection strategy for triazabutadiene is presented. It affords enhanced synthetic and practical utility of triazabutadiene. The effects steric electronic factors in rate removal discussed, compatible with traditional acid‐labile used solid phase peptide...

This work describes the development of phenyl diazenyl piperidine triazene derivatives that can be activated to release aryl diazonium ions for labeling proteins using light. These probes show marked bench stability at room temperature and photoisomerized via low-intensity UVA irradiation physiological pH. Upon isomerization, triazenes are rendered more basic readily protonate reactive ions. It was discovered intensity duration UV light essential observed ion reactivity in competition with...