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Chemical Science
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ARTICLE
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functionalization of TMTHSI with a wide variety of linkers
allowing attachment of a diversity of small molecules and
(peptide, nucleic acid) biologics. In our opinion, the very
attractive functionalization possibilities, combined with its
great reactivity and small size offer opportunities for TMHSI to
become the standard for non-copper catalyzed click reactions
in a multitude of applications.
DOI: 10.1039/D0SC03477K
99.
A. Kuzmin, A. Poloukhtine, M. A. Wolfert, V. V. Popik,
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10 The biological response induced by the steric bulk and
lipophilicity is known as the "observer effect" see S. B.
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Conflicts of interest
There are no conflicts to declare.
12 a) J. Dommerholt, O. van Rooijen, A. Borrmann, C. Fonseca
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Acknowledgements
Cristal Therapeutics financially supported this work. J. Walther,
E. Hebels and B. Mesquita from Utrecht University are
gratefully acknowledged for their assistance with the cellular
uptake experiment of Cy7 functionalized nanoparticles.
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Notes and references
‡ An all carbon 7-membered ring system is likely to be too
strained, therefore unstable and synthetically not accessible, but
a 7-membered ring containing longer bonds due to the presence
of carbon-hetero atom bonds and therefore less strained, was
apparently synthetically feasible.14
§
Although aromatic azides especially containing electron
withdrawing groups turned out to be very reactive in the strain
promoted click reaction with BCN,[12a] benzylazide was chosen as
a reference compound, since a majority of APIs used for
preparing azide derivatives will be aliphatic ones.
18 M. King, R. Baati, A. Wagner, Chem. Comm. 2012, 48, 9308-
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19 M. Frings, C. Bolm, A. Blum, C. Gnamm, Eur. J. Med. Chem.
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§§ Although the click reaction went smoothly, it seems -
according to NMR - that slowly one indole part of the dye is
reduced, possible by the presence of formate.
20 T. L. Gilchrist, C. J. Moody, Chem. Rev. 1977, 77, 409-435.
21 T. Yoshimura, T. Omata, N. Furukawa, S. Oae, J. Org. Chem.
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§§§ Folic Acid BCN was capable of a strain promoted click
reaction with an azide in DMSO and the click product remained
stable upon further dilution with aqueous buffer. However,
when Folic Acid BCN in DMSO was mixed with an azide
containing compound in aqueous buffer no click reaction
occurred. Possibly, due to an intramolecular reaction within Folic
Acid the cyclopropane ring of BCN opened up, rendering the
compound no longer capable to perform a click reaction.
22 W. Frank, P .K. Claus, Monatshefte für Chemie 1990, 121
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23 A. Tota, M. Zenzola, S. J. Chawner, S. St John-Campbell, C.
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vs19.0) ClogP (3.4) was similar to DBCO.
27 a) Q. Hu, C. J. Rijcken, R. Bansal, W. E. Hennink, G. Storm, J.
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X. Ning, J. Guo, M.A. Wolfert, G. J. Boons, Angew. Chem.
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,
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