- Azepine- or Azocine-Embedded Hexabenzocoronene Derivatives as Nitrogen-Doped Saddle or Saddle-Helix Nanographenes
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Two novel nitrogen-doped, hexa-peri-hexabenzocoronene (HBC)-based nanographenes (NGs) 1 and 2 bearing an azepine and an azocine at the fjord region, respectively, were synthesized and characterized. Notably, structure 1 was synthesized by Diels–Alder reac
- An, Peng,He, Run-Ying,Li, Ranran,Ma, Bin,Xiao, Ming-Jun,Zhang, Bin,Zhang, Yi-Kang
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supporting information
p. 24478 - 24483
(2021/10/19)
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- Highly Efficient Multigram Synthesis of Dibenzoazacyclooctyne (DBCO) without Chromatography
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The synthesis of 4-[11,12-didehydrodibenzo[b,f]azocin-5(6H)-yl]-4-oxobutanoic acid, also known as dibenzoazacyclooctyne (DBCO) or aza-dibenzocyclooctyne (ADIBO), was optimized for large-scale preparations of at least 10 g with an overall yield of 42%.
- McNelles, Stuart A.,Pantaleo, Julia L.,Adronov, Alex
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p. 2740 - 2745
(2019/11/21)
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- STEROIDS AND PROTEIN-CONJUGATES THEREOF
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Described herein protein steroid conjugates that are useful, for example, for the target-specific delivery of glucocorticoids (GCs) to cells.
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- A Compact and Synthetically Accessible Fluorine-18 Labelled Cyclooctyne Prosthetic Group for Labelling of Biomolecules by Copper-Free Click Chemistry
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A new fluorine-containing azadibenzocyclooctyne (ADIBO-F) was designed using a synthetically accessible pathway. The fluorine-18 prosthetic group was prepared from its toluenesulfonate precursor and isolated in 21–35 % radiochemical yield in 30 minutes of synthetic time. ADIBO-F has been incorporated into azide-functionalized, cancer-targeting peptides through a strain-promoted alkyne–azide cycloaddition with high radiochemical yields and purities. The final products are novel peptide-based positron emission tomography (PET) imaging agents that possess high affinities for their targets, growth hormone secretagogue receptor 1a (GHSR-1a) and gastrin-releasing peptide receptor (GRPR), with IC50 values of 9.7 and 0.50 nm, respectively. This is a new and rapid labelling option for the incorporation of fluorine-18 into biomolecules for PET imaging.
- Murrell, Emily,Kovacs, Michael S.,Luyt, Leonard G.
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p. 1625 - 1628
(2018/07/31)
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- A two-step strategy to radiolabel choline phospholipids with99mTc in S180 cell membranes via strain-promoted cyclooctyne–azide cycloaddition reaction
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As tumor markers, the radiolabeling of choline (Cho)-containing phospholipids in cellular membranes with99mTc is a challenge. The conventional strategy to combine the metallic radionuclide with Cho by large ligand damages the bioactivity of Cho, resulting in low tumor-to-nontumor ratios. Pretargeting strategy based on strain-promoted cyclooctyne–azide cycloaddition (SPAAC) reaction was applied to solve this general problem. Functional click synthons were synthesized as pretargeting components: azidoethyl-choline (AECho) serves as tumor marker and azadibenzocyclooctyne (ADIBO) conjugated to bis(2-pieolyl) amine (BPA) ligand (ADIBO-BPA) as99mTc(CO)3-labeling and azido-binding group. Both in vitro cell experiment and in vivo biodistribution experiment indicate that it is versatile to radiolabel Cho in cellular membranes via this two-step pretargeting strategy. We believe that this pretargeting strategy can indeed enhance the target-specificity and also reduce background signals to optimize imaging quality.
- Chen, Qingxin,Chu, Taiwei
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p. 5472 - 5475
(2016/11/09)
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- BIOMOLECULE CONJUGATES
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The present invention relates to biomolecule conjugates which comprise a biomolecule wherein at least one non-natural amino acid (NNAA) is integral to the structure of the biomolecule and wherein the NNAA is a point of attachment of a linker to which a payload, particularly a cytotoxic agent, is attached. More specifically, this invention relates to conjugates of cell-binding agents and active release products comprising cytotoxic agents wherein the conjugates are produced by means of a cycloaddition reaction. Methods of production, pharmaceutical compositions and methods of use are provided.
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Page/Page column 79
(2016/06/28)
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- Scalable synthesis of strained cyclooctyne derivatives
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Modifications to the Popik synthesis of aza-dibenzocyclooctyne (DIBAC) derivatives are described, which avoids tedious purifications and dramatically improves the yield. A new and analogous route to biarylazacyclooctynone (BARAC) through an amide disconnection was also attempted. The BARAC derivatives prepared were found to be unstable under the conditions employed, undergoing a known rearrangement. Finally, the synthesis of a difluoro-DIBAC derivative with a second-order rate constant intermediate between DIBAC and BARAC derivatives (0.50 M-1) is described. While more difficult to synthesize, this molecule was found to be considerably more stable than any BARAC derivatives that were prepared. Georg Thieme Verlag Stuttgart New York.
- Chadwick, Ryan C.,Van Gyzen, Sabrina,Liogier, Sophie,Adronov, Alex
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p. 669 - 677
(2014/03/21)
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- Pd-catalyzed ring assembly by vinylation and intramolecular heck coupling: A versatile strategy towards functionalized azadibenzocyclooctynes
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A new modular approach based on Pd-catalyzed C-C bond formation is presented for the assembly of a benzannulated azocine scaffold, the key intermediate in the synthesis of functionalized azadibenzocyclooctynes (aza-DIBOs). The intramolecular ring-closing Heck coupling was investigated by variation of the C-X bond. The reaction rate is limited by the initial oxidative addition step and the regiochemistry strongly depends on the auxiliary phosphine. Under optimized conditions, the 8-endo regioisomer was obtained in 71 % yield over two steps (with no protecting group chemistry) or in one pot, inclusive of C-N bond formation. The practical generation of the octyne triple bond of a prototypical N-benzoyl aza-DIBO, without the need for chromatographic purification, is also described. The structural features, including those of the ring-strained cyclic octyne, were elucidated by NMR spectroscopy and X-ray crystallographic analysis. The high reactivity of the N-benzoyl aza-DIBO synthesized is demonstrated in a strain-promoted azide-alkyne cycloaddition reaction with an alkyl azide (k=0.38 M-1 s-1). Copyright
- J?ger, Michael,G?rls, Helmar,Günther, Wolfgang,Schubert, Ulrich S.
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p. 2150 - 2157
(2013/03/28)
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- Strain-promoted azide-alkyne cycloaddition with ruthenium(II)-azido complexes
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The reactivity of an exemplary ruthenium(II)-azido complex towards non-activated, electron-deficient, and towards strain-activated alkynes at room temperature and low millimolar azide and alkyne concentrations has been investigated. Non-activated terminal and internal alkynes failed to react under such conditions, even under copper(I) catalysis conditions. In contrast, as expected, rapid cycloaddition was observed with electron-deficient dimethyl acetylenedicarboxylate (DMAD) as the dipolarophile. Since DMAD and related propargylic esters are excellent Michael acceptors and thus unsuitable for biological applications, we investigated the reactivity of the azido complex towards cycloaddition with derivatives of cyclooctyne (OCT), bicyclo[6.1.0]non-4-yne (BCN), and azadibenzocyclooctyne (ADIBO). While no reaction could be observed in the case of the less strained cyclooctyne OCT, the highly strained cyclooctynes BCN and ADIBO readily reacted with the azido complex, providing the corresponding stable triazolato complexes, which were amenable to purification by conventional silica gel column chromatography. An X-ray crystal structure of an ADIBO cycloadduct was obtained and verified that the formed 1,2,3-triazolato ligand coordinates the metal center through the central N2 atom. Importantly, the determined second-order rate constant for the ADIBO cycloaddition with the azido complex (k2=6.9 × 10 -2 M-1 s-1) is comparable to the rate determined for the ADIBO cycloaddition with organic benzyl azide (k 2=4.0 × 10-1 M-1 s-1). Our results demonstrate that it is possible to transfer the concept of strain-promoted azide-alkyne cycloaddition (SPAAC) from purely organic azides to metal-coordinated azido ligands. The favorable reaction kinetics for the ADIBO-azido-ligand cycloaddition and the well-proven bioorthogonality of strain-activated alkynes should pave the way for applications in living biological systems.
- Cruchter, Thomas,Harms, Klaus,Meggers, Eric
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p. 16682 - 16689
(2014/01/06)
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- AZA-DIBENZOCYCLOOCTYNES AND METHODS OF MAKING AND USING SAME
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Convenient methods of preparing aza-dibenzocyclooctynes are disclosed herein. Aza-dibenzocyclooctynes attached to a surface are also disclosed herein. Aza-dibenzocyclooctynes can be reacted with azides to form heterocyclic compounds. Such reactions can be useful in a wide variety of applications including, for example, labeling surfaces.
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- Strain-promoted "click" modification of a mesoporous metal-organic framework
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Strain-promoted "click" chemistry is used to post-synthetically modify the pore walls of azide-functionalized mesoporous bio-MOF-100 (N 3-bio-MOF-100). The reactions proceed in high yield and produce no byproduct. This new method was used to introduce various functional groups into the MOF mesopores, including succinimidyl ester bioconjugation moieties that allow for straightforward coupling of biomolecules to the pore walls.
- Liu, Chong,Li, Tao,Rosi, Nathaniel L.
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p. 18886 - 18888
(2013/01/15)
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- Copper-free click for PET: Rapid 1,3-dipolar cycloadditions with a fluorine-18 cyclooctyne
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The strain-promoted click 1,3-dipolar cycloaddition reactions involving azides and cyclooctynes for the synthesis of triazoles offer the advantage of being able to be performed in biological settings via copper-free chemistries. While strained reagents conjugated to optical dyes and radiometal conjugates have been reported, cyclooctyne reagents labeled with fluorine-18 ( 18F) and radiochemically evaluated in a copper-free click reaction have yet to be explored. This report describes the conversion of a bifunctional azadibenzocyclooctyne (ADIBO) amine to the 18F-labeled cyclooctyne 4, the subsequent fast copper-free 1,3-dipolar cycloaddition reaction with alkyl azides at 37 °C (>70% radiochemical conversion in 30 min), and biological evaluations (serum stability of >95% at 2 h). These findings demonstrate the excellent reactivity of the 18F-labeled cyclooctyne 4 with readily available azides that will allow future work focusing on rapid copper-free in vitro and in vivo click chemistries for PET imaging using 18F-labeled cyclooctyne derivatives of ADIBO.
- Carpenter, Richard D.,Hausner, Sven H.,Sutcliffe, Julie L.
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p. 885 - 889
(2012/02/01)
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- Strain-promoted copper-free "click" chemistry for 18F radiolabeling of bombesin
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Click for PET: The GRP-receptor-specific peptide bombesin, which is often used for nuclear imaging of tumors, can be labeled with 18F in a mild and rapid manner by using a copper-free azide-alkyne "click" reaction. A range of azides can be used to provide peptides with different hydrophobicities. The resulting 18F radiopharmaceutical tracers (see scheme) maintain their high affinity for the targeted receptor in vitro in human prostate cancer cells. Copyright
- Campbell-Verduyn, Lachlan S.,Mirfeizi, Leila,Schoonen, Anne K.,Dierckx, Rudi A.,Elsinga, Philip H.,Feringa, Ben L.
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p. 11117 - 11120
(2012/02/02)
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- Aza-dibenzocyclooctynes for fast and efficient enzyme PEGylation via copper-free (3+2) cycloaddition
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A strained aza-dibenzocyclooctyne was prepared via a high-yielding synthetic route. Copper-free, strain-promoted click reaction with azides showed excellent kinetics, and a functionalised aza-cyclooctyne was applied in fast and efficient PEGylation of enzymes.
- Debets, Marjoke F.,Van Berkel, Sander S.,Schoffelen, Sanne,Rutjes, Floris P. J. T.,Van Hest, Jan C. M.,Van Delft, Floris L.
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supporting information; experimental part
p. 97 - 99
(2010/04/01)
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- Surface functionalization using catalyst-free azide-alkyne cycloaddition
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The utility of catalyst-free azide-alkyne [3 + 2] cycloaddition for the immobilization of a variety of molecules onto a solid surface and microbeads was demonstrated. In this process, the surfaces are derivatized with aza-dibenzocyclooctyne (ADIBO) for the immobilization of azide-tagged substrates via a copper-free click reaction. Alternatively, ADIBO-conjugated molecules are anchored to the azide-derivatized surface. Both immobilization techniques work well in aqueous solutions and show excellent kinetics under ambient conditions. We report an efficient synthesis of aza-dibenzocyclooctyne (ADIBO), thus far the most reactive cyclooctyne in cycloaddition to azides. We also describe convenient methods for the conjugation of ADIBO with a variety of molecules directly or via a PEG linker.
- Kuzmin, Alexander,Poloukhtine, Andrei,Wolfert, Margreet A.,Popik, Vladimir V.
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p. 2076 - 2085
(2011/07/09)
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